2-spiro-5- and 6-hydroxamic acid indanes as hdac inhibitors

ABSTRACT

The present invention is directed to inhibitors of histone deacetylases (HDACs) such as HDAC6, and their use in the treatment of diseases such as cell proliferative diseases (e.g., cancer), neurological (e.g., neurodegenerative disease or neurodevelopmental disease), inflammatory or autoimmune disease, infection, metabolic disease, hematologic disease, or cardiovascular disease.

RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. provisionalapplication No. 62/351,399, filed Jun. 17, 2016, the entire contents ofwhich are incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to inhibitors of zinc-dependent histonedeacetylases (HDACs) useful in the treatment of diseases or disordersassociated with HDACs including cell proliferation diseases (e.g.,cancer), neurological and inflammatory diseases. Specifically, thisinvention is concerned with compounds and compositions inhibiting HDACs,methods of treating diseases associated with HDACs, and methods ofsynthesizing these compounds.

BACKGROUND OF THE INVENTION

Many members of the HDAC family require zinc (Zn) to function properly.For instance, the isozyme histone deacetylase 6 (HDAC6) is azinc-dependent historic deacetylase that possesses histone deacetylaseactivity. Other family members include HDACs 1-5 and 7-11. (De Ruijteret al., Biochem. J. 2003. 370; 737-749).

HDAC6 is known to deacetylate and associate with α-tubulin, cortactin,heat shock protein 90, ß-catenin, glucose-regulated protein 78 kDa,myosin heavy chain 9, heat shock cognate protein 70, and dnaJ homology;subfamily A member 1 (reviewed in Li et al., FEBS J. 2013, 280: 775-93;Zhang et al., Protein Cell. 2015, 6(1): 42-54). Diseases in which HDAC6inhibition could have a potential benefit include cancer (reviewed inAldana-Masangkay et al., J. Biomed Biotechnol. 2011, 875824),specifically: multiple myeloma (Hideshima et al., Proc. Natl. Acad. Sci.USA 2005, 102 (24): 8567-8572); lung cancer (Kamemura et al., Biochem.Biophys. Res. Commun. 2008, 374(1):84-89); ovarian cancer (Bazzaro etal., Clin. Cancer Res. 2008, 14(22):7340-7347); breast cancer (Lee etal., Cancer Res. 2008, 68(18):7561-7569; Park et al., Oncol. Rep. 2011,25: 1677-81; Rey et al., Eur. J. Cell Biol. 2011, 90: 128-35); prostatecancer (Seidel et al., Biochem. Pharmacol. 2015 (15)00714-5); pancreaticcancer (Nawrocki et al., Cancer Res. 2006, 66(7):3773-3781); renalcancer (Cha et al., Clin. Cancer Res. 2009, 15(3): 840-850);hepatocellular cancer (Ding et al., FEBS Lett. 2013, 587:880-6; Kanno etal., Oncol. Rep. 2012, 28: 867-73); lymphomas (Ding et al., Cancer CellInt. 2014, 14:139; Amengual et al., Clin Cancer Res. 2015,21(20):4663-75); and leukemias such as acute myeloid leukemia (AML)(Fiskus et al., Blood 2008, 112(7):2896-2905) and acute lymphoblasticleukemia (ALL) (Rodriguez-Gonzalez et al., Blood 2008, 1 12(1 1):Abstract 1923)).

Inhibition of HDAC6 may also have a role in cardiovascular disease,including pressure overload, chronic ischemia, andinfarction-reperfusion injury (Tannous et al., Circulation 2008, 117(24):3070-3078); bacterial infection, including those caused byuropathogenic Escherichia coli (Dhakal and Mulve, J. Biol. Chem. 2008,284(1):446-454); neurological diseases caused by accumulation ofintracellular protein aggregates such as Alzheimer's, Parkinson's andHuntington's disease (reviewed in Simoes-Pires et al., Mol.Neurodegener. 2013, 8: 7) or central nervous system trauma caused bytissue injury, oxidative-stress induced neuronal or axomal degeneration(Rivieccio et al., Proc. Natl. Acad. Sci. USA 2009,106(46):19599-195604); and inflammation and autoimmune diseases throughenhanced T cell-mediated immune tolerance at least in part througheffects on regulatory T cells, including rheumatoid arthritis,psoriasis, spondylitis arthritis, psoriatic arthritis, multiplesclerosis, lupus, colitis and graft versus host disease (reviewed inWang et al., Nat. Rev. Drug Disc. 2009 8(12):969-981; Vishwakarma etal., Int. Immunopharmacol. 2013, 16:72-8; Kalin et al., J. Med. Chem.2012, 55:639-51); and fibrotic disease, including kidney fibrosis (Choiet al., Vascul. Pharmacol. 2015 72:130-140).

Four HDAC inhibitors are currently approved for the treatment of somecancers. These are suberanilohydroxamic acid (Vorinostat; Zolinza®) forthe treatment of cutaneous T cell lymphoma and multiple myeloma;Romidepsin (FK228; FR901228; Istodax®) for the treatment of peripheral Tcell lymphoma; Panobinostat (LBH-589; Farydak®) for the treatment ofmultiple myeloma; and belinostat (PXD101; Beleodaq®) for the treatmentof peripheral T cell lymphoma. However, these drugs are of limitedeffectiveness and can give rise to unwanted side effects. Thus there isa need for HDAC inhibitors with an improved safety-efficacy profile.

SUMMARY OF THE INVENTION

One aspect of the invention relates to compounds of Formula I:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, or isomers thereof, wherein:

X¹, X², X³, X⁴, X⁵, and X⁶ are each independently, at each occurrence,—CR¹R²—, —NR³—, —O—, —C(O)—, —S(O)₂—, —S(O)—, or —S—;

Y¹, Y², Y³ and Y⁴ are each independently, at each occurrence, N or CR¹,wherein the hydroxamic acid is attached at Y² or Y³ and Y² or Y³ is acarbon atom when attached to the hydroxamic acid;

L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—;

R is independently —H, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₄-C₈cycloalkenyl,—C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₅-C₁₂spirocycloalkyl, heterocyclyl,spiroheterocyclyl, aryl, or heteroaryl containing 1-5 heteroatomsselected from the group consisting of N, S, P, or O, wherein each alkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkyl, spirocycloalkyl,heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more —OH, halogen, oxo, —NO₂, —CN, —R¹, R²,—SR³, —OR³, —NHR³, —NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R¹, —C(O)R¹, —CO₂R¹,—NR³S(O)₂R¹, —S(O)R¹, —S(O)NR³R⁴, —NR³S(O)R⁴, heterocyclyl, aryl, orheteroaryl;

R¹ and R² are independently, at each occurrence, —H, —R³, —R⁴,—C₁-C₆alkyl, —C₂-C₆alkenyl, —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl,—C₃-C₈cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5heteroatoms selected from the group consisting of N, S, P and O, —OH,halogen, —NO₂, —CN, —NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂,—S(O)₂N(C₁-C₆alkyl)₂, —N(C₁-C₆alkyl)S(O)₂R⁵, —S(O)₂(C₁-C₆alkyl),—(C₁-C₆alkyl)S(O)₂R⁵, —C(O)C₁-C₆alkyl, —CO₂C₁-C₆alkyl,—N(C₁-C₆alkyl)S(O)₂C₁-C₆alkyl, or —(CHR⁵)_(p)NR³R⁴, wherein each alkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more —OH, halogen,—NO₂, oxo, —CN, —R⁵, —OR³, —NHR³, —NR³R⁴, —S(O)₂N(R³)₂—, —S(O)₂R⁵,—C(O)R⁵, —CO₂R⁵, —NR³S(O)₂R⁵, —S(O)R⁵, —S(O)NR³R⁴, —NR³S(O)R⁵,heterocyclyl, aryl, or heteroaryl;

or R¹ and R² can combine with the carbon atom to which they are bothattached to form a cycloalkyl, heterocycle, spirocycloalkyl,spiroheterocycle, or spirocycloalkenyl;

or R¹ and R², when on adjacent or non-adjacent atoms, can combine toform a heterocycle, cycloalkyl, aryl, heteroaryl containing 1-5heteroatoms selected from the group consisting of N, S, P and O, orcycloalkenyl;

R³ and R⁴ are independently, at each occurrence, —H, —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl,heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected fromN, S, P, and O, —S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂(C₁-C₆alkyl),—(C₁-C₆alkyl)S(O)₂R⁵, —C(O)C₁-C₆alkyl, —CO₂C₁-C₆alkyl, or—(CHR⁵)_(p)N(C₁-C₆alkyl)₂, wherein each alkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted with one or more substituents selected from —OH, halogen,—NO₂, oxo, —CN, —R⁵, —O(C₁-C₆)alkyl, —NH(C₁-C₆)alkyl, —N(C₁-C₆alkly)₂,—S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂NHC₁-C₆alkyl, —C(O)C₁-C₆alkyl,—CO₂C₁-C₆alkyl, —N(C₁-C₆alkyl)S(O)₂C₁-C₆alkyl, —S(O)R⁵,—S(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆alkyl)S(O)R⁵, heterocyclyl, aryl, orheteroaryl;

R⁵ is independently, at each occurrence, —H, —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₄-C₈cycloalkenyl, heterocyclyl, aryl, heteroaryl containing 1-5heteroatoms selected from N, S, P and O, —OH, halogen, —NO₂, —CN,—NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl),—S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂C₁-C₆alkyl, —C(O)C₁-C₆alkyl, —CO₂C₁-C₆alkyl,—N(C₁-C₆alkyl)SO₂C₁-C₆alkyl, —S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂,—N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl) or —(CH₂)_(p)N(C₁-C₆alkyl)₂;

p is 0, 1, 3, 4, 5, of 6;

n is 0, 1, 2, 3, or 4;

m is 0, 1, or 2; and

wherein the sum m+n<≤4.

Another aspect of the invention relates to a method of treating adisease or disorder associated with HDAC6 modulation in a subject inneed thereof, comprising administering to the subject an effectiveamount of a compound of Formula I.

Another aspect of the invention is directed to a method of inhibiting ahistone deacetylase (e.g., a zinc-dependent histone deacetylase such asHDAC6). The method involves administering to a patient in need thereofan effective amount of a compound of Formula I. In some embodiments, themethod of treating a disease or disorder associated with HDAC6modulation in a subject includes inhibiting a histone deacetylase (e.g.,a zinc-dependent histone deacetylase such as HDAC6) in the subject.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula I and a pharmaceuticallyacceptable carrier. The pharmaceutically acceptable carrier can furtherinclude an excipient, diluent, or surfactant. The pharmaceuticalcomposition can be effective for treating a disease or disorderassociated with HDAC6 modulation in a subject in need thereof. Thepharmaceutical compositions can comprise the compounds of the presentinvention for use in treating diseases described herein. Thecompositions can contain at least one compound of the invention and apharmaceutically acceptable carrier.

Another aspect of the present disclosure relates to a compound ofFormula I, or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, for use in treating orpreventing a disease associated with HDAC6 modulation. The inventionalso provides the use of the compounds described herein in themanufacture of a medicament for the treatment of a disease associatedwith HDACs.

The present invention also provides methods for the treatment of humandiseases or disorders including, without limitation, on cologi cal,neurological, inflammatory, autoimmune, infectious, metabolic,hematologic, or cardiovascular diseases or disorders.

The present invention also provides compounds that are useful ininhibiting of zinc-dependent HDAC enzymes, for instance HDAC6. Thesecompounds can also be useful in the treatment of diseases includingcancer.

The present invention further provides compounds that can inhibit HDAC6.In some embodiments, the efficacy-safety profile of the compounds of thecurrent invention can be improved relative to other known HDAC (e.g.HDAC6) inhibitors. Additionally, the present technology also has theadvantage of being able to be used for a number of different types ofdiseases, including cancer and non-cancer indications. Additionalfeatures and advantages of the present technology will be apparent toone of skill in the art upon reading the Detailed Description of theInvention, below.

DETAILED DESCRIPTION OF THE INVENTION

HDAC6 is a zinc-dependent histone deacetylase that has two catalyticdomains. HDAC6 can interact with and deacetylate non-histone proteins,including HSP90 and α-tubulin. Acetylation of HSP90 is associated withloss of function of HSP90. HDAC6 is also implicated in the degradationof misfolded proteins as part of the aggresome. Accordingly, inhibitionof HDAC6 can have downstream effects that can play a role in thedevelopment of certain diseases such as cancer. The present inventionprovides inhibitors of HDAC6 and methods for using the same to treatdisease.

In a first aspect of the invention, compounds of Formula I aredescribed:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, and isomers thereof, wherein Y¹, Y², Y³, Y⁴, X¹, X², X³, X⁴,X⁵, X⁶, L, R, m and n are described as above.

The details of the invention are set forth in the accompanylngdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, illustrative methods and materials are now described.Other features, objects, and advantages of the invention will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs. All patents and publications cited in thisspecification are incorporated herein by reference in their entireties.

Definitions

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a givenchemical moiety (e.g. an alkyl group) can (but is not required to) bebonded other substituents (e.g. heteroatoms). For instance, an alkylgroup that is optionally substituted can be a fully saturated alkylchain (i.e. a pure hydrocarbon). Alternatively, the same optionallysubstituted alkyl group can have substituents different from hydrogen.For instance, it can, at any point along the chain be bonded to ahalogen atom, a hydroxyl group, or any other substituent describedherein. Thus the term “optionally substituted” means that a givenchemical moiety has the potential to contain other functional groups,but does not necessarily have any further fiinctional groups.

The term “aryl” refers to cyclic, aromatic hydrocarbon groups that have1 to 2 aromatic rings, including monocyclic or bicyclic groups such asphenyl, biphenyl or naphthyl. Where containing two aromatic rings(bicyclic, etc.), the aromatic rings of the aryl group may be joined ata single point (e.g., biphenyl), or fused (e.g., naphthyl). The arylgroup may be optionally substituted by one or more substituents, e.g., 1to 5 substituents, at any point of attachment. Exemplary substituentsinclude, but are not limited to, —H, -halogen, —O—C₁-C₆alkyl,—C₁-C₆alkyl, —OC₂-C₆alkenyl, —OC₂-C₆alkynyl, —C₂-C₆alkenyl,—C₂-C₆alkynyl, —OH, —OP(O)(OH)₂, —OC(O)C₁-C₆alkyl, —C(O)C₁-C₆alkyl,—OC(O)OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂,—S(O)₂—C₁-C₆alkyl, —S(O)NHC₁-C₆alkyl, and —S(O)N(C₁-C₆alkyl)₂. Thesubstituents can themselves be optionally substituted. Furthermore whencontaining two fused rings the aryl groups herein defined may have anunsaturated or partially saturated ring fused with a fully saturatedring. Exemplary ring systems of these aryl groups include indanyl,indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.

Unless otherwise specifically defined, “heteroaryl” means a monovalentmonocyclic aromatic radical or a polycyclic aromatic radical of 5 to 24ring atoms, containing one or more ring heteroatoms selected from N, S,P, and O, the remaining ring atoms being C. Heteroaryl as herein definedalso means a bicyclic heteroaromatic group wherein the heteroatom isselected from N, S, P, and O. The aromatic radical is optionallysubstituted independently with one or more substituents describedherein. Examples include, but are not limited to, furyl, thienyl,pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl,oxazolyl, oxadiazolyl, pyrazinyl, indolyl thiophen-2-yl, quinolyl,benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole,benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl,imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl,indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl,pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl,thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl,indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl,benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl,dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl,1,6-naphthyridinyl, benzo[de]isoquinolinyl,pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl,tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl,pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl,pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl,3,4-dihydro-2H-1λ²-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene,pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl,1H-pyrido[3,4-b][1,4]thiazinyl, benzooxazolyl, benzoisoxazolyl,furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl,furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl,[1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl,benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one,3,4-dihydro-2H-pyrazolo [1,5-b][1,2]oxazinyl,4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl,imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl,and derivatives thereof. Furthermore when containing two fused rings theheteroaryl groups herein defined may have an unsaturated or partiallysaturated ring fused with a fully saturated ring. Exemplary ring systemsof these heteroaryl groups include indolinyl, indolinonyl,dihydrobenzothiophenyl, dihydroben.zofuran, chromanyl, thiochromanyl,tetrahydroquinolinyl, dihydrobenzothiazine,3,4-dihydro-1H-4soquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl,and dihydrobenzoxanyl.

“Alkyl” refers to a straight or branched chain saturated hydrocarbon.C₁-C₆alkyl groups contain 1 to 6 carbon atoms. Examples of a C₁-C₆alkylgroup include, but are not limited to, methyl, ethyl, propyl, butyl,pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl andneopentyl.

The term “alkenyl” means an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Certain alkenyl groupshave 2 to about 4 carbon atoms in the chain. Branched means that one ormore lower alkyl groups such as methyl, ethyl, or propyl are attached toa linear alkenyl chain. Exemplary alkenyl groups include ethenyl,propenyl, n-butenyl, and i-butenyl. A C₂-C₆ alkenyl group is an alkenylgroup containing between 2 and 6 carbon atoms.

The term “alkynyl” means an aliphatic hydrocarbon group containing acarbon-carbon triple bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Certain alkenyl groupshave 2 to about 4 carbon atoms in the chain. Branched means that one ormore lower alkyl groups such as methyl, ethyl, or propyl are attached toa linear alkynyl chain. Exemplary alkenyl groups include ethynyl,propynyl, n-butyryl, 2-butynyl, 3-methylbutynyl, and n-pentynyl. A C₂-C₆alkynyl group is an alkynyl group containing between 2 and 6 carbonatoms.

The term “cycloalkyl” means monocyclic or polycyclic saturated carbonrings containing 3-18 carbon atoms. Examples of cycloalkyl groupsinclude, without limitations, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl,bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl. A C₃-C₈ cycloalkyl is acycloalkyl group containing between 3 and 8 carbon atoms. A cycloalkylgroup can be fused (e.g., decalin) or bridged (e.g., norbornane).

The term “cycloalkenyl” means monocyclic, non-aromatic unsaturatedcarbon rings containing 4-18 carbon atoms. Examples of cycloalkenylgroups include, without limitation, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl, and norborenyl. A C₄-C₈ cycloalkenyl is acycloalkenyl group containing between 4 and 8 carbon atoms.

The terms “heterocyclyl” or “heterocycloalkyl” or “heterocycle” refer tomonocyclic or polycyclic 3 to 24-membered rings containing carbon andheteroatoms taken from oxygen, phosphorous nitrogen, or sulfur andwherein there is not delocalized π electrons (aromaticity) shared amongthe ring carbon or heteroatoms. Heterocyclyl rings include, but are notlimited to, oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl,oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl,thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide,piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.A heteroycyclyl or heterocycloalkyl ring can also be fused or bridged,e.g., can be a bicyclic ring.

As used herein, the term “halo” or “halogen” means a fluoro, chloro,bromo, or iodo group.

The term “carbonyl” refers to a functional group composing a carbon atomdouble-bonded to an oxygen atom. It can be abbreviated herein as C(O),or as C═O.

The term “oxo” refers to an oxygen atom that is double-bonded to anotheratom. An “oxo” group can be connected to a carbon atom (e.g., to form acarbonyl, as defined above) or can be connected to a heteroatom such assulfur (e.g., to form a sulfoxide or a sulfone) or phosphorous (e.g., toform a phosphorous ylide).

“Spirocycle” means carbogenic bicyclic ring systems with both ringsconnected through a single atom. A “spirocycloalkyl” or “spirocyclic”system is a spirocycle in which both rings are fully carbogenic. Thering can be different in size and nature, or identical in size andnature. Examples include spiropentane, spirohexane, spiroheptane,spirooctane, spirononane, or spirodecane. One or both of the rings in aspirocycle can be fused to another carbocyclic, heterocyclic, aromatic,or heteroaromatic ring. One or more of the carbon atoms in thespirocycle can be substituted with a heteroatom (e.g., O, N, S, or P). AC₅-C₁₂ spirocycle is a spirocycle containing between 5 and 12 carbonatoms. One or more of the carbon atoms can be substituted with aheteroatom.

The term “spirocyclic heterocycle” “spiroheterocyclyl” or“spiroheterocycle” is understood to mean a spirocycle wherein at leastone of the rings is a heterocycle (e.g., at least one of the rings isfuranyl, morpholinyl, or piperadinyl). A spirocyclic heterocycle cancontain between 5 and 12 atoms, at least one of which is a heteroatomselected from N, O, S and P. Spiroheterocycloalkyl groups can be forinstance, without limitation, azapiroheptanes; azaspirooctanes;azaspirononanes; azaspirodecanes; oxaspiroheptanes; oxaspirooctanes;octaspirononanes; or oxaspirodecanes.

The disclosure also includes pharmaceutical compositions comprising aneffective amount of a disclosed compound and a pharmaceuticallyacceptable carrier. Representative “pharmaceutically acceptable salts”include, e.g., water-soluble and water-insoluble salts, such as theacetate, amsonate (4,4-diaminostilbene-2,2-disulfonate),benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate,bromide, butyrate, calcium, calcium edetate, camsylate, carbonate,chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate,estolate, esylate, fiunarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, sethionate,lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt,3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate(1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate,phosphate/diphosphate, picrate, polygalacturonate, propionate,p-toluenesulfonate, salicylate, stearate, subacetate, succinate,sulfate, sulfosalicylate, suramate, tannate, tartrate, teociate,tosylate, triethiodide, and valerate salts.

The term “tautomers” refers to a set of compounds that have the samenumber and type of atoms, but differ in bond connectivity and are inequilibrium with one another. A “tautomer” is a single member of thisset of compounds. Typically a single tautomer is drawn but it isunderstood that this single structure is meant to represent all possibletautomers that might exist. Examples include enol-ketone tautomerism.When a ketone is drawn it is understood that both the enol and ketoneforms are part of the invention.

The term “prodrug,” as used in this disclosure, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to adisclosed compound. Furthermore, as used herein a prodrug is a drugwhich is inactive in the body, but is transformed in the body typicallyeither during absorption or after absorption from the gastrointestinaltract into the active compound. The conversion of the prodrug into theactive compound in the body may be done chemically or biologically(i.e., using an enzyme).

The term “solvate” refers to a complex of variable stoichiometry formedby a solute and solvent. Such solvents for the purpose of the inventionmay not interfere with the biological activity of the solute. Examplesof suitable solvents include, but are not limited to, water, MeOH, EtOH,and AcOH. Solvates wherein water is the solvent molecule are typicallyreferred to as hydrates. Hydrates include compositions containingstoichiometric amounts of water, as well as compositions containingvariable amounts of water.

The term “isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers). Withregard to stereoisomers, the compounds of Formula I may have one or moreasymmetric carbon atom and may occur as racemates, racemic mixtures andas individual enantiomers or diastereomers.

The term “stereoisomers” refers to the set of compounds which have thesame number and type of atoms and share the same bond connectivitybetween those atoms, but differ in three dimensional structure. The term“stereoisomer” refers to any member of this set of compounds. Forinstance, a stereoisomer may be an enantiomer or a diastereomer.

The term “enantiomers” refers to a pair of stereoisomers which arenon-superimposable mirror images of one another. The term “enantiomer”refers to a single member of this pair of stereoisomers. The term“racemic” refers to a 1:1 mixture of a pair of enantiomers.

The term “diastereomers” refers to the set of stereoisomers which cannotbe made superimposable by rotation around single bonds. For example,cis- and trans- double bonds, endo— and exo- substitution on bicyclicring systems, and compounds containing multiple stereogenic centers withdifferent relative configurations are considered to be diastereomers.The term “diastereomer” refers to any member of this set of compounds.In some examples presented, the synthetic route may produce a singlediastereomer or a mixture of diastereomers. In some cases thesediastereomers were separated and in other cases a wavy bond is used toindicate the structural element where configuration is variable.

An “effective amount” when used in connection with a compound is anamount effective for treating or preventing a disease in a subject asdescribed herein.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating includes curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or composition to the subject, which can form an equivalentamount of active compound within the subject's body.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guineapig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

In one or more embodiments of the compounds of Formula I, n is 0 and mis 1.

In one or more embodiments of the compounds of Formula I, n is 1 and mis 1.

In one or more embodiments of the compounds of Formula I, X⁵ is C(O).

In one or more embodiments of the compounds of Formula I, L is a bond.In one or more embodiments, L is —(CR¹R²)_(p)—. In one or moreembodiments, L is —C(O)NR³—. In one or more embodiments, L is —S(O)₂—.In one or more embodiments, L is —S(O)₂NR³—. In one or more embodiments,L is —S(O)—. In one or more embodiments, L is —S(O)NR³—. In one or moreembodiments, L is —C(O)(CR¹R²)_(p)O—. In one or more embodiments, L is—C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula I, the compoundis of the Formula IA:

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—.In one or more embodiments, X¹ is —CH₂— and X² is —CH₂—. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, and X³ is —CH₂—. In one or moreembodiments, X¹is —CH₂—, X² is —CH₂—, X³ is —CH₂— and X⁴ is —CH₂—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂— and X⁵ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is —CH₂—. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶is —CH₂— and m is 0. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 0 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 andn is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, is X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶is —CH₂—, m is 0 and n is 2. In any of the above-embodiments, L is abond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —NH—.In one or more embodiments, X¹ is —NH— and X² is —CH₂—. In one or moreembodiments, X¹ is —NH—, X² is —CH₂—, and X³ is —CH₂—. In one or moreembodiments, X¹ is —NH—, X² is —CH₂—, X³ is —CH₂— and X⁴ is —CH₂—. Inone or more embodiments, X¹ is NH—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂— and X⁵ is —CH₂—. In one or more embodiments, X¹ is —NH—, X² is—CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is —CH₂—. In one ormore embodiments, X¹ is —NH—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶is —CH₂— and m is 0. In one or more embodiments, X¹ is —NH—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 0 and n is 0. In one or moreembodiments, X¹ is —NH—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —NH—, X² is—CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In oneor more embodiments, X¹ is —NH—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—,X⁶ is —CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —NH—,X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2.In one or more embodiments, X¹ is —NH—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one or more embodiments, X¹ is—NH—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and nis 2. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —NH—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —NH—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —NH—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —NH—, X² is—CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In one or more embodiments, X¹ is —NH—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —NH—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —NH—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —NH—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —O—. Inone or more embodiments, X¹ is —O— and X² is —CH₂—. In one or moreembodiments, X¹ is —O—, X² is —CH₂—, and X³ is —CH₂—. In one or moreembodiments, X¹ is —O—, X² is —CH₂—, X³ is —CH₂— and X⁴ is —CH₂—. In oneor more embodiments, X¹ is —O—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—and X⁵ is —CH₂—. In one or more embodiments, X¹ is —O—, X² is X³ is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X6 is —CH₂—. In one or moreembodiments, X¹ is —O—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂— and m is 0. In one or more embodiments, X¹ is —O—, X² is —CH₂—, X⁴is —CH₂—, X⁵ is —CH₂—, m is 0 and n is 0. In one or more embodiments, X¹is —O—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and nis 1. In one or more embodiments, X¹ is —O—, X² is —CH₂—, X⁴ is —C(O)—,X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or more embodiments,X¹ is —O—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0and n is 1. In one or more embodiments, X¹ is —O—, X² is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one or moreembodiments, X¹ is —O—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 2. In one or more embodiments, X¹ is —O—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In anyof the above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—,—S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or—C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —O—, X²is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 1.In one or more embodiments, X¹ is —O—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments, X¹ is—O—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, mis 1 and n is 1. In one or more embodiments, X¹ is —O—, X² is —CH₂—, X³is X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In one or more embodiments, X¹ is —O—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —O—, X²is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —O—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —O—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —C(O)—.In one or more embodiments, X¹ is —C(O)— and X² is —CH₂—. In one or moreembodiments, X¹ is —C(O)—, X² is —CH₂—, and X³ is —CH₂—. In one or moreembodiments, X¹ is —C(O)—, X² is —CH₂—, X³ is —CH₂— and X⁴ is —CH₂—. Inone or more embodiments, X¹ is —C(O)—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂— and X⁵ is —CH₂—. In one or more embodiments, X¹ is —C(O)—, X² is—CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is —CH₂—. In one ormore embodiments, X¹ is —C(O)—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—,X⁶ is —CH₂— and m is 0. In one or more embodiments, X¹ is —C(O)—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 0 and n is 0. In one or moreembodiments, X¹ is —C(O)—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —C(O)—, X²is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. Inone or more embodiments, X¹ is —C(O)—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In one or more embodiments, X¹is —C(O)—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0and n is 2. In one or more embodiments, X¹ is —C(O)—, X² is —CH₂—, X⁴ is—C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one or moreembodiments, X¹ is —C(O)—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is—CH₂—, m is 0 and n is 2. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —C(O)—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments, X¹ is—C(O)—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—,m is 1 and n is 1. In one or more embodiments, X¹ is —C(O)—, X² is—CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In one or more embodiments, X¹ is —C(O)—, X² is —CH₂—, X³ is—CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In anyof the above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—,—S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or—C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —C(O)—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —C(O)—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —C(O)—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is—S(O)₂—. In one or more embodiments, X¹ is —S(O)₂— and X² is —CH₂—. Inone or more embodiments, X¹ is —S(O)₂—, X² is —CH₂—, and X³ is —CH₂—. Inone or more embodiments, X¹ is —S(O)₂—, X² is —CH₂—, X³ is —CH₂— and X⁴is —CH₂—. In one or more embodiments, X¹ is —S(O)₂—, X² is —CH₂—, X³ is—CH₂—, X⁴ is —CH₂— and X⁵ is —CH₂—. In one or more embodiments, X¹ is—S(O)₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is—CH₂—. In one or more embodiments, X¹ is —S(O)₂—, X² is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0. In one or more embodiments,X¹ is —S(O)₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 0 and n is 0.In one or more embodiments, X¹ is —S(O)₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or more embodiments, X¹is —S(O)₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0and n is 1. In one or more embodiments, X¹ is —S(O)₂—, X² is —CH₂—, X⁴is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —S(O)₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 2. In one or more embodiments, X¹ is —S(O)₂—, X²is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. Inone or more embodiments, X¹ is —S(O)₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—C(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In any of the above-embodiments,L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is—S(O)₂—, X² is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—and m is 1. In one or more embodiments, X¹ is —S(O)₂—, X² is —CH₂—, X³is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —S(O)₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is—S(O)₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —S(O)₂—, X²is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1and n is 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is—S(O)₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is—CH₂—, m is 1 and n is 2. In one or more embodiments, X¹ is —S(O)₂—, X²is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —S(O)₂—, X² is —CH₂—, X³is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. Inany of the above-embodiments, L is a bond, —(CR¹R²)_(p)—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —S(O)—.In one or more embodiments, X¹ is —S(O)— and X² is —CH₂—. In one or moreembodiments, X¹ is —S(O)—, X² is —CH₂—, and X³ is —CH₂—. In one or moreembodiments, X¹ is —S(O)—, X² is —CH₂—, X³ is —CH₂— and X⁴ is —CH₂—. Inone or more embodiments, X¹ is —S(O)—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂— and X⁵ is —CH₂—. In one or more embodiments, X¹ is —S(O)—, X² is—CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is —CH₂—. In one ormore embodiments, X¹ is —S(O)—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—,X⁶ is —CH₂— and m is 0. In one or more embodiments, X¹ is —S(O)—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 0 and n is 0. In one or moreembodiments, X¹ is —S(O)—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —S(O)—, X²is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. Inone or more embodiments, X¹ is —S(O)—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In one or more embodiments, X¹is —S(O)—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂——, X⁶ is —CH₂—, m is 0and n is 2. In one or more embodiments, X¹ is —S(O)—, X² is —CH₂—, X⁴ is—C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one or moreembodiments, X¹ is —S(O)—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is—CH₂—, m is 0 and n is 2. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —S(O)—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —S(O)—, X² is —CH₂—, X³ is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —S(O)—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is—S(O)—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —S(O)—, X²is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1and n is 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —S(O)—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —S(O)—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —S(O)—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —S—. Inone or more embodiments, X¹ is —S— and X² is —CH₂—. In one or moreembodiments, X¹ is —S—, X² is —CH₂—, and X³ is —CH₂—. In one or moreembodiments, X¹ is —S—, X² is —CH₂—, X³ is —CH₂— and X⁴ is —CH₂—. In oneor more embodiments, X¹ is —S—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—and X⁵ is —CH₂—. In one or more embodiments, X¹ is —S—, X² is —CH₂—, X³is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is —CH₂—. In one or moreembodiments, X¹ is —S—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂— and m is 0. In one or more embodiments, X¹ is —S—, X² is —CH₂—, X⁴is —CH₂—, X⁵ is —CH₂—, m is 0 and n is 0. In one or more embodiments, X¹is —S—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and nis 1. In one or more embodiments, X¹ is —S—, X² is —CH₂—, X⁴ is —C(O)—,X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or more embodiments,X¹ is —S—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0and n is 1. In one or more embodiments, X¹ is —S—, X² is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one or moreembodiments, X¹ is —S—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 2. In one or more embodiments, X¹ is —S—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In anyof the above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—,—S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or—C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —S—, X²is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 1.In one or more embodiments, X¹ is —S—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments, X¹ is—S—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, mis 1 and n is 1. In one or more embodiments, X¹ is —S—, X² is —CH₂—, X³is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. Inone or more embodiments, X¹ is —S—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —S—, X²is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —S—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —S—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—and X² is —NH—. In one or more embodiments, X¹ is —CH₂—, X² is —NH—, andX³ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is —NH—, X³ is—CH₂— and X⁴ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—NH—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —CH₂—. In one or moreembodiments, X¹ is —CH₂—, X² is —NH—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—NH—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —NH—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —NH—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —NH—, X⁴ is —C(O)—, X⁴ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—NH—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In oneor more embodiments, X¹ is —CH₂—, X² is —NH—, X⁴ is —CH₂—, X⁵ is —CH₂—,X⁶ is —CH₂—, m is 0 and n is 2. In one or more embodiments, X¹ is —CH₂—,X² is —NH—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2.In one or more embodiments, X¹ is —CH₂—, X² is —NH—, X⁴ is —CH₂—, X⁵ is—C(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In any of the above-embodiments,L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —NH—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —NH—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —NH—, X³ is —CH₂—, X⁴ is —CH₂, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—NH—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In one or more embodiments, X¹ is —CH₂—, X² is —NH—, X³ is —CH₂—,X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —NH—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —NH—. X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —CH₂—, X² is —NH—, X³ is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or—C(O)(CR¹R²)_(p)O—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—and X² is —O—. In one or more embodiments, X¹ is —CH₂—, X² is —O—, andX³ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is —O—, X³ is—CH₂— and X⁴ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—O—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —CH₂—. In one or moreembodiments, X¹ is —CH₂—, X² is —O—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—O—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —O—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —O—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —O—, X⁴ is —C(O)—, X³ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—O—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In oneor more embodiments, X¹ is —CH₂—, X² is —O—, X⁴ is —CH₂—, X⁵ is —CH₂—,X⁶ is —CH₂—, m is 0 and n is 2. In one or more embodiments, X¹ is —CH₂—,X² is —O—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —O—, X⁴ is —CH₂—, X⁵ is—C(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In any of the above-embodiments,L is a bond, —(CR¹R²)_(p)—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —O—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —O—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —O—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—O—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In one or more embodiments, X¹ is —CH₂—, X² is —O—, X³ is —CH₂—,X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —O—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —O—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —CH₂—, X² is —O—, X³ is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—and X₂ is —C(O)—. In one or more embodiments, X¹ is —CH₂—, X₂ is —C(O)—,and X³ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X₂ is —C(O)—,X³ is —CH₂— and X⁴ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X₂is —C(O)—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —CH₂—. In one or moreembodiments, X¹ is —CH₂—, X₂ is —C(O)—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X₂ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X₂ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X₂ is —C(O)—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X₂ is —C(O)—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X₂ is—C(O)—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. Inone or more embodiments, X¹ is —CH₂—, X₂ is —C(O)—, X⁴ is —CH₂, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one or more embodiments, X¹ is—CH₂—, X₂ is —C(O)—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 andn is 2. In one or more embodiments, X¹ is —CH₂—, X₂ is —C(O)—, X⁴ is—CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X₂ is —C(O)—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X₂ is —C(O)—, X³ is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X₂ is —C(O)—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is—CH₂—, X₂ is —C(O)—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X₂ is—C(O)—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 andn is 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X₂ is —C(O)—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X₂ is —C(O)—, X³is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X₂ is —C(O)—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—and X² is —S(O)₂—. In one or more embodiments, X¹ is —CH₂—, X² is—S(O)₂—, and X³ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—S(O)₂—, X³ is —CH₂— and X⁴ is —CH₂—. In one or more embodiments, X¹ is—CH₂—, X² is —S(O)₂—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —CH₂—. In oneor more embodiments, X¹ is —CH₂—, X² is —S(O)₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is—CH₂—, X² is —S(O)₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0.In one or more embodiments, X¹ is —CH₂—, X² is —S(O)₂—, X⁴ is —CH₂—, X⁵is —CH₂—, m is 0 and n is 0. In one or more embodiments, X¹ is —CH₂—, X²is —S(O)₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. Inone or more embodiments, X¹ is —CH₂—, X² is —S(O)₂—, X⁴ is —C(O)—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is—CH₂—, X² is —S(O)₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 andn is 1. In one or more embodiments, X¹ is —CH₂—, X² is —S(O)—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one or moreembodiments, X¹ is —CH₂—, X² is —S(O)₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶is —CH₂—, m is 0 and n is 2. In one or more embodiments, X¹ is —CH₂—, X²is —S(O)₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 2.In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—,—S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or—C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —S(O)₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —S(O)₂—, X³ is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —S(O)₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is—CH₂—, X² is —S(O)₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—S(O)₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 andn is 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —S(O)₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —S(O)₂—, X³is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —S(O)₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—and X² is —S(O)—. In one or more embodiments, X¹ is —CH₂—, X² is —S(O)—,and X³ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is —S(O)—,X³ is —CH₂— and X⁴ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X²is —S(O)—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —CH₂—. In one or moreembodiments, X¹ is —CH₂—, X² is —S(O)—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—S(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —S(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —S(O)—, X⁴ is—CH₂—, X⁵ is —CH₂, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —S(O)—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—S(O)—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. Inone or more embodiments, X¹ is —CH₂—, X² is —S(O)—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one or more embodiments, X¹ is—CH₂—, X² is —S(O)—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 andn is 2. In one or more embodiments, X¹ is —CH₂—, X² is —S(O)—, X⁴ is—CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —S(O)—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —S(O)—, X³ is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —S(O)—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is—CH₂—, X² is —S(O)—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—S(O)—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 andn is 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —S(O)—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —S(O)—, X³is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —S(O)—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X₆ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—and X² is —S—. In one or more embodiments, X¹ is —CH₂—, X² is —S—, andX³ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is —S—, X³ is—CH₂— and X⁴ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—S—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —CH₂—. In one or moreembodiments, X¹ is —CH₂—, X² is —S—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—S—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —S—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —S—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —S—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—S—, X⁴ is —CH²—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In oneor more embodiments, X¹ is —CH₂—, X² is —S—, X⁴ is —CH₂—, X⁵ is —CH₂—,X⁶ is —CH₂—, m is 0 and n is 2. In one or more embodiments, X¹ is —CH₂—,X² is —S—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —S—, X⁴ is —CH₂—, X⁵ is—C(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In any of the above-embodiments,L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —S—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —S—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —S—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—S—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In one or more embodiments, X¹ is —CH₂—, X² is —S—, X³ is —CH₂—,X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —S—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —S—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —CH₂—, X² is —S—, X³ is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, and X³ is —NH—. In one or more embodiments, X¹ is —CH₂—, X²is —CH₂—, X³ is —NH— and X⁴ is —CH₂—. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X³ is —NH—, X⁴ is —CH₂— and X⁵ is —CH₂—. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —NH—, X⁴ is —CH₂—, X⁵is —CH₂— and X⁶ is —CH₂—. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —NH—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —NH—,X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —NH—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —NH—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁶ is —CH₂—, m is 1 and n is 2.In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —NH—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, and X³ is —O—. In one or more embodiments, X¹ is —CH₂—, X²is —CH₂—, X³ is —O— and X⁴ is —CH₂—. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X³ is —O—, X⁴ is —CH₂— and X⁵ is —CH₂—. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —O—, X⁴ is —CH₂—, X⁵is —CH₂— and X⁶ is —CH₂—. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —O—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —O—,X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —O—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —O—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —O—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—O—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any ofthe above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, and X³ is —S—. In one or more embodiments, X¹ is —CH₂—, X²is —CH₂—, X³ is —S— and X⁴ is —CH₂—. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X³ is —S—, X⁴ is —CH₂— and X⁵ is —CH₂—. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —S—, X⁴ is —CH₂—, X⁵is —CH₂— and X⁶ is —CH₂—. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —S—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —S—,X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —S—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —S—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —S—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—S—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any ofthe above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, and X³ is —C(O)—. In one or more embodiments, X¹ is —CH₂—,X² is —CH₂—, X³ is —C(O)— and X⁴ is —CH₂—. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂— and X⁵ is —CH₂—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is—CH₂—, X⁵ is —CH₂— and X⁶ is —CH₂—. In any of the above-embodiments, Lis a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —C(O)—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In any of the above-embodiments,L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is1 and n is 2. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, and X³ is —S(O)₂—. In one or more embodiments, X¹ is —CH₂—,X² is —CH₂—, X³ is —S(O)₂— and X⁴ is —CH₂—. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —S(O)₂—, X⁴ is —CH₂— and X⁵ is —CH₂—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —S(O)₂—, X⁴ is—CH₂—, X⁵ is —CH₂— and X⁶ is —CH₂—. In any of the above-embodiments, Lis a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —S(O)₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—S(O)₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —S(O)₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X³ is —S(O)₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —S(O)₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³is —S(O)₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —S(O)₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, and X³ is —S(O)—. In one or more embodiments, X¹ is —CH₂—,X² is —CH₂—, X³ is —S(O)— and X⁴ is —CH₂—. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —S(O)—, X⁴ is —CH₂— and X⁵ is —CH₂—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —S(O)—, X⁴ is—CH₂—, X⁵ is —CH₂— and X⁶ is —CH₂—. In any of the above-embodiments, Lis a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —S(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—S(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —S(O)—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X³ is —S(O)—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —S(O)—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³is —S(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —S(O)—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂— and X⁴ is —NH—. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —NH— and X⁵ is —CH₂—. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —NH—,X⁵ is —CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X²is —CH₂—, X⁴ is —NH—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —NH—, X⁵ is —CH₂—, mis 0 and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—,X⁴ is —NH—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —NH₂—, X⁵ is —C(O)—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —NH—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —NH—, X⁵ is —C(O)—,X⁶ is —CH₂—, m is 0 and n is 2. In any of the above-embodiments, L is abond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —NH—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —NH—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —NH—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —C(O)—, X⁴ is —NH—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —NH—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —NH—, X⁵ is —CH₂—, X⁶ is m is 1 and n is 2. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —NH—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of the above-embodiments,L is a bond, —(CR¹R2)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂— and X⁴ is —O—. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —O— and X⁵ is —CH₂—. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —O—, X⁵is —CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —O—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —O—, X⁵ is —CH₂—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—O—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —O—, X⁵ is —C(O)—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —O—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —O—, X⁵ is —C(O)—, X⁶is —CH₂—, m is 0 and n is 2. In any of the above-embodiments, L is abond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —O—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —O—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —O—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —C(O)—, X⁴ is —O—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —O—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —O—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —O—,X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂— and X⁴ is —S—. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —S— and X⁵ is —CH₂—. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —S—, X⁵is —CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —S—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —S—, X⁵ is —CH₂—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—S—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —S—, X⁵ is —C(O)—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —S—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —S—, X⁵ is —C(O)—, X⁶is —CH₂—, m is 0 and n is 2. In any of the above-embodiments, L is abond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —S—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —S—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —S—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —C(O)—, X⁴ is —S—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In any of the above-embodiments L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, is —CH₂—, X²is —CH₂—, X³ is —CH₂—, X⁴ is —S—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1 andn is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —S—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —S—,X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂— and X⁴ is —C(O)—. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)— and X⁵ is —CH₂—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—C(O)—, X⁵ is —CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0.In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵is —CH₂—, m is 0 and n is 0. In one or more embodiments, X¹ is —CH₂—, X²is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is—C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —C(O)—, C⁶ is —CH₂—, m is 0and n is 2. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —C(O)—, X¹ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —C(O)—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In any of the above-embodiments,L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³is —C(O)—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂— and X⁴ is —S(O)₂—. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —S(O)₂— and X⁵ is —CH₂—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—S(O)₂—, X⁵ is —CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X⁴ is —S(O)₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0.In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —S(O)₂—, X⁵is —CH₂—, m is 0 and n is 0. In one or more embodiments, X¹ is —CH₂—, X²is —CH₂—, X⁴ is —S(O)₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —S(O)₂—, X⁵ is—C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X⁴ is —S(O)₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—S(O)₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —S(O)₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —S(O)₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —S(O)₂—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —S(O)₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —CH₂—, X⁴ is —S(O)₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 andn is 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —S(O)₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³is —C(O)—, X⁴ is —S(O)₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2.In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—S(O)₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂— and X⁴ is —S(O)—. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —S(O)— and X⁵ is —CH₂—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—S(O)—, X⁵ is —CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X⁴ is —S(O)—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0.In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —S(O)—, X⁵is —CH₂—, m is 0 and n is 0. In one or more embodiments, X¹ is —CH₂—, X²is —CH₂—, X⁴ is —S(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —S(O)—, X⁵ is—C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X⁴ is —S(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—S(O)—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —S(O)—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —S(O)—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —S(O)—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —S(O)—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —CH₂—, X⁴ is —S(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —S(O)—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³is —C(O)—, X⁴ is —S(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—S(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —NH—. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—NH— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —NH—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —NH—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—CH₂—, X⁵ is —NH—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —NH—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —NH—, X⁶ is —CH₂—, m is 0 and n is 2. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —NH—,X⁶ is —CH₂—, m is 0 and n is 2. In any of the above-embodiments, L is abond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —NH—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —NH—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —NH—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —NH—, X⁶ is —CH₂—, m is 1 and nis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —C(O)—, X⁵ is —NH—, X⁶ is —CH₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —NH—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—CH₂—, X⁴ is —CH₂—, X⁵ is —NH—, X⁶ is —CH₂—, m is 1 and n is 2. In anyof the above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—,—S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or—C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —O—. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—O— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —O—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —O—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—CH₂—, X⁵ is —O—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —O—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —O—, X⁶ is —CH₂—, m is 0 and n is 2. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —O—, X⁶is —CH₂—, m is 0 and n is 2. In any of the above-embodiments, L is abond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —O—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —O—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —O—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —O—, X⁶ is —CH₂—, m is 1 and nis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —C(O)—, X⁵ is —O—, X⁶ is —CH₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —O—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—CH₂—, X⁴ is —CH₂—, X⁵ is —O—, X⁶ is —CH₂—, m is 1 and n is 2. In any ofthe above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —S—. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—S— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —S—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —S—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—CH₂—, X⁵ is —S—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —S—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —S—, X⁶ is —CH₂—, m is 0 and n is 2. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —S—, X⁶is —CH₂—, m is 0 and n is 2. In any of the above-embodiments, L is abond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —S—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —S—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —S—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —S—, X⁶ is —CH₂—, m is 1 and nis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —C(O)—, X⁵ is —S—, X⁶ is —CH₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —S—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—CH₂—, X⁴ is —CH₂—, X⁵ is —S—, X⁶ is —CH₂—, m is 1 and n is 2. In any ofthe above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —C(O)—. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—C(O)— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—C(O)—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —C(O)—, X⁶ is—CH₂—, m is 0 and n is 2. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —C(O)—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—C(O)—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1 andn is 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³——C(O)(CR¹R²)_(p)O—, or—C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is1 and n is 2. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —S(O)₂—. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—S(O)₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —S(O)₂—, X⁶ is —CH₂— and m is 0. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —S(O)₂—,m is 0 and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—,X⁴ is —CH₂—, X⁵ is —S(O)₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —S(O)₂—,X⁶ is —CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—,X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —S(O)₂—, X⁶ is —CH₂—, m is 0 and n is 1.In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—S(O)₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —S(O)₂—, X⁶ is —CH₂—, m is 0and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—CH₂—, X⁵ is —S(O)₂—, X⁶ is —CH₂—, m is 0 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —S(O)₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —S(O)₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—S(O)₂—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —S(O)₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —S(O)₂—, X⁶ is —CH₂—, m is 1 andn is 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —S(O)₂—, X⁶ is —CH₂—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³is —C(O)—, X⁴ is —CH₂—, X⁵ is —S(O)₂—, X⁶ is —CH₂—, m is 1 and n is 2.In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —S(O)₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —S(O)—. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—S(O)— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —S(O)—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —S(O)—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—CH₂—, X⁵ is —S(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —S(O)—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —S(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—S(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —S(O)—, X⁶ is —CH₂—, m is 0and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—CH₂—, X⁵ is —S(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —S(O)—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —S(O)—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—S(O)—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —S(O)—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —S(O)—, X⁶ is —CH₂—, m is 1 andn is 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is S(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —S(O)—, X⁶ is —CH₂—, m is 1 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —S(O)—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is —NH—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —NH— and m is 0. In one or more embodiments, X¹ is —CH₂—,X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —NH—, m is 0 and n is 1. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is—CH₂—, X⁶ is —NH—, m is 0 and n is 1. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —NH—, m is 0 and nis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —NH—, m is 0 and n is 2. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CO—, X⁵ is —CH₂—, X⁶ is —NH—, m is 0and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—CH₂—, X⁵ is —C(O)—, X⁶ is —NH—, m is 0 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR —, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —NH— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —NH—, m is 1 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —NH—, m is 1 and n is 1. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —NH—,m is 1 and n is 1. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —NH—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —NH—, m is 1 and n is 2. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —NH—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is —O—. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—,X⁶ is —O— and m is 0. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —O—, m is 0 and n is 1. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—,X⁶ is —O—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—,X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —O—, m is 0 and n is 1. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —O—, m is 0 and n is 2.. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —O—, m is 0 and nis 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—,X⁵ is —C(O)—, X⁶ is —O—, m is 0 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —O— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —O—, m is 1 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —O—, m is 1 and n is 1. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —O—, mis 1 and n is 1. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —O—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —O—, m is 1 and n is 2. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —O—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is —C(O)—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —C(O)— and m is 0. In one or more embodiments, X¹ is —CH₂—,X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —C(O)—, m is 0 and n is 1.In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵is —CH₂—, X⁶ is —C(O)—, m is 0 and n is 1. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —C(O)—, m is0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴is —CH₂—, X⁵ is —CH₂—, X⁶ is —C(O)—, m is 0 and n is 2. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is—C(O)—, m is 0 and n is 2. In one or more embodiments, X¹ is —CH₂—, X²is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —C(O)—, m is 0 and n is 2. Inany of the above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—,—S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or—C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —C(O)— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —C(O)—, m is 1 and n is 1. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —C(O)—, m is 1 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In any of the above-embodiments,L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —C(O)—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³is —C(O)−, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —C(O)—, m is 1 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —C(O)—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is —S(O)₂—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —S(O)₂— and m is 0. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)₂—, m is 0 andn is 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—C(O)—, X⁵ is —CH₂—, X⁶ is —S(O)₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is—S(O)₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X²is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)₂—, m is 0 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is—CH₂—, X⁶ is —S(O)₂—, m is 0 and n is 2. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —S(O)₂—, m is 0and n is 2. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)₂—, m is 1 and n is 1. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —S(O)₂—, m is 1 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is—CH₂—, X⁶ is —S(O)₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —S(O)₂—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)₂—, m is 1 and n is 2.In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X6 is —S(O)₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is —S(O)—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —S(O)— and m is 0. In one or more embodiments, X¹ is —CH₂—,X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)—, m is 0 and n is 1.In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵is —CH₂—, X⁶ is —S(O)—, m is 0 and n is 1. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —S(O)—, m is0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴is —CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)—, m is 0 and n is 2. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is—S(O)—, m is 0 and n is 2. In one or more embodiments, X¹ is —CH₂—, X²is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —S(O)—, m is 0 and n is 2. Inany of the above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—,—S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or—C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)—, m is 1 and n is 1. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —S(O)—, m is 1 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is—CH₂—, X⁶ is —S(O)—, m is 1 and n is 1. In any of the above-embodiments,L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —S(O)—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)—, m is 1 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is —S—. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—,X⁶ is —S— and m is 0. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S—, m is 0 and n is 1. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—,X⁶ is —S—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—,X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —S—, m is 0 and n is 1. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —S—, m is 0 and n is 2. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —S—, m is 0 and nis 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—,X⁵ is —C(O)—, X⁶ is —S—, m is 0 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S—, m is 1 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —S—, m is 1 and n is 1. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —S—, mis 1 and n is 1. In any of the above-embodiments, L is a bond,—(CRW)_(p) C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, X¹ is —CH₂—,X² is —CH₂, X³ is —CH₂, X⁴ is —CH₂, X⁵ is —C(O)—, X⁶ is —S—, m is 1 andn is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S—, m is 1 and n is 2. In oneor more embodiments, X¹ is —CH₂, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —S—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IA, the compoundis of the formula IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, or IA-8:

In one or more embodiments, of the compounds of Formula I, the compoundis of the Formula IB:

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—.In one or more embodiments, X¹ is —CH₂— and X² is —CH₂—. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, and X³ is —CH₂—. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂— and X⁴ is —CH₂—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂— and X⁵ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is —CH₂—. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶is —CH₂— and m is 0. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X³ is —CH₂—, m is 0 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—C(O)—, X⁵ is —CH₂—, m is 0 and n is 1. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 andn is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is—CH₂—, m is 0 and n is 2. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —NH—.In one or more embodiments, X¹ is —NH— and X² is —CH₂—. In one or moreembodiments, X¹ is —NH—, X² is —CH₂—, and X³ is —CH₂—. In one or moreembodiments, X¹ is —NH—, X² is —CH₂—, X³ is —CH₂— and X⁴ is —CH₂—. Inone or more embodiments, X¹ is —NH—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂— and X⁵ is —CH₂—. In one or more embodiments, X¹ is —NH—, X² is—CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is —CH₂—. In one ormore embodiments, X¹ is —NH—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶is —CH₂— and m is 0. In one or more embodiments, X¹ is —NH—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 0 and n is 0. In one or moreembodiments, X¹ is —NH—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂— m is 0 and n is 1. In one or more embodiments, X¹ is —NH—, X² is—CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In oneor more embodiments, X¹ is —NH—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—,X⁶ is —CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —NH—,X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2.In one or more embodiments, X¹ is —NH—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one or more embodiments, X¹ is—NH—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and nis 2. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —NH—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —NH—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —NH—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —NH—, X² is—CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In one or more embodiments, X¹ is —NH—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —NH—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —NH—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —NH—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —O—. Inone or more embodiments, X¹ is —O— and X² is —CH₂—. In one or moreembodiments, X¹ is —O—, X² is —CH₂—, and X³ is —CH₂—. In one or moreembodiments, X¹ is —O—, X² is —CH₂—, X³ is —CH₂— and X⁴ is —CH₂—. In oneor more embodiments, X¹ is —O—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—and X⁵ is —CH₂—. In one or more embodiments, X¹ is —O—, X² is —CH₂—, X³is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X6 is —CH₂—. In one or moreembodiments, X¹ is —O—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂— and m is 0. In one or more embodiments, X¹ is —O—, X² is —CH₂—, X⁴is —CH₂—, X⁵ is —CH₂—, m is 0 and n is 0. In one or more embodiments, X¹is —O—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and nis 1. In one or more embodiments, X¹ is —O—, X² is —CH₂—, X⁴ is —C(O)—,X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or more embodiments,X¹ is —O—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0and n is 1. In one or more embodiments, X¹ is —O—, X² is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one or moreembodiments, X¹ is —O—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 2. In one or more embodiments, X¹ is —O—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X6 is —CH₂—, m is 0 and n is 2. In anyof the above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—,—S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or—C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —O—, X²is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 1.In one or more embodiments, X¹ is —O—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments, X¹ is—O—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, mis 1 and n is 1. In one or more embodiments, X¹ is —O—, X² is —CH₂—, X³is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. Inone or more embodiments, X¹ is —O—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —O—, X²is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —O—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —O—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —C(O)—.In one or more embodiments, X¹ is —C(O)— and X² is —CH₂—. In one or moreembodiments, X¹ is —C(O)—, X² is —CH₂—, and X³ is —CH₂—. In one or moreembodiments, X¹ is —C(O)—, X² is —CH₂—, X³ is —CH₂— and X⁴ is —CH₂—. Inone or more embodiments, X¹ is —C(O)—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂— and X⁵ is —CH₂—. In one or more embodiments, X¹ is —C(O)—, X² is—CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is —CH₂—. In one ormore embodiments, X¹ is —C(O)—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—,X⁶ is —CH₂— and m is 0. In one or more embodiments, X¹ is —C(O)—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 0 and n is 0. In one or moreembodiments, X¹ is —C(O)—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —C(O)—, X²is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. Inone or more embodiments, X¹ is —C(O)—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In one or more embodiments, X¹is —C(O)—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0and n is 2. In one or more embodiments, X¹ is —C(O)—, X² is —CH₂—, X⁴ is—C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one or moreembodiments, X¹ is —C(O)—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is—CH₂—, m is 0 and n is 2. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —C(O)—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —C(O)—, X² is —CH₂—, X³ is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —C(O)—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is—C(O)—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —C(O)—, X²is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1and n is 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —C(O)—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —C(O)—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —C(O)—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is—S(O)₂—. In one or more embodiments, X¹ is —S(O)₂— and X² is —CH₂—. Inone or more embodiments, X¹ is —S(O)₂—, X² is —CH₂—, and X³ is —CH₂—. Inone or more embodiments, X¹ is —S(O)₂—, X² is —CH₂—, X³ is —CH₂— and X⁴is —CH₂—. In one or more embodiments, X¹ is —S(O)₂—, X² is —CH₂—, X³ is—CH₂—, X⁴ is —CH₂— and X⁵ is —CH₂—. In one or more embodiments, X¹ is—S(O)₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is—CH₂—. In one or more embodiments, X¹ is —S(O)₂—, X² is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0. In one or more embodiments,X¹ is —S(O)—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 0 and n is 0.In one or more embodiments, X¹ is —S(O)₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or more embodiments, X¹is —S(O)₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0and n is 1. In one or more embodiments, X¹ is —S(O)₂—, X² is —CH₂—, X⁴is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is S(O)₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 2. In one or more embodiments, X¹ is —S(O)₂—, X²is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. Inone or more embodiments, X¹ is —S(O)₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—C(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In any of the above-embodiments,L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR ¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is—S(O)₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—and m is 1. In one or more embodiments, X¹ is —S(O)₂—, X² is —CH₂—, X³is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —S(O)₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is—S(O)₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —S(O)₂—, X²is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1and n is 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is—S(O)₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is—CH₂—, m is 1 and n is 2. In one or more embodiments, X¹ is —S(O)₂—, X²is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —S(O)₂—, X² is —CH₂—, X³is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. Inany of the above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—,—S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or—C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —S(O)—.In one or more embodiments, X¹ is —S(O)— and X² is —CH₂—. In one or moreembodiments, X¹ is —S(O)—, X² is —CH₂—, and X³ is —CH₂—. In one or moreembodiments, X¹ is —S(O)—, X² is —CH₂—, X³ is —CH₂— and X⁴ is —CH₂—. Inone or more embodiments, X¹ is —S(O)—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂— and X⁵ is —CH₂—. In one or more embodiments, X¹ is —S(O)—, X² is—CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, and X⁶ is —CH₂—. In one ormore embodiments, X¹ is —S(O)—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—,X⁶ is —CH₂— and m is 0. In one or more embodiments, X¹ is —S(O)—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 0 and n is 0. In one or moreembodiments, X¹ is —S(O)—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —S(O)—, X²is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. Inone or more embodiments, X¹ is —S(O)—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In one or more embodiments, X¹is —S(O)—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0and n is 2. In one or more embodiments, X¹ is —S(O)—, X² is —CH₂—, X⁴ is—C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one or moreembodiments, X¹ is —S(O)—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is—CH₂—, m is 0 and n is 2. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —S(O)—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —S(O)—, X² is —CH₂—, X³ is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —S(O)—, X² is —CH₂—, X³ is —CH₂—, X⁴ —CH₂—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is—S(O)—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —S(O)—, X²is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1and n is 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R2)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —S(O)—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —S(O)—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —S(O)—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X^(I) is —S—.In one or more embodiments, X¹ is —S— and X² is —CH₂—. In one or moreembodiments, X¹ is —S—, X² is —CH₂—, and X³ is —CH₂—. In one or moreembodiments, X¹ is —S—, X² is —CH₂—, X³ is —CH₂— and X⁴ is —CH₂—. In oneor more embodiments, X¹ is —S—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—and X⁵ is —CH₂—. In one or more embodiments, X¹ is —S—, X² is —CH₂—, X³is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is —CH₂—. In one or moreembodiments, X¹ is —S—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂— and m is 0. In one or more embodiments, X¹ is —S—, X² is —CH₂—, X⁴is —CH₂—, X⁵ is —CH₂—, m is 0 and n is 0. In one or more embodiments, X¹is —S—, X² is —CH₂—, X⁴ is is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0and n is 1. In one or more embodiments, X¹ is —S—, X² is —CH₂—, X⁴ is—C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —S—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —S—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In oneor more embodiments, X¹ is —S—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—,X⁶ is —CH₂—, m is 0 and n is 2. In one or more embodiments, X¹ is —S—,X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 2.In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—,—S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or—C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹is —S—, X²is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 1.In one or more embodiments, X¹ is —S—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments, X¹ is—S—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, mis 1 and n is 1. In one or more embodiments, X¹ is —S—, X² is —CH₂—, X³is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. Inone or more embodiments, X¹ is —S—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —S—, X²is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —S—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —S—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—and X² is —NH—. In one or more embodiments, X¹ is —CH₂—, X² is —NH—, andX³ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is —NH—, X³ is—CH₂— and X⁴ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—NH—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —CH₂—. In one or moreembodiments, X¹ is —CH₂—, X² is —NH—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—NH—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —NH—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —NH—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —NH—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—NH—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In oneor more embodiments, X¹ is —CH₂—, X² is —NH—, X⁴ is —CH₂—, X⁵ is —CH₂—,X⁶ is —CH₂—, m is 0 and n is 2. In one or more embodiments, X¹ is —CH₂—,X² is —NH—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is ——CH₂—, m is 0 and n is 2.In one or more embodiments, X¹ is —CH₂—, X² is —NH—, X⁴ is —CH₂—, X⁵ is—C(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In any of the above-embodiments,L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —NH—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —NH—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —NH—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—NH—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In one or more embodiments, X¹ is —CH₂—, X² is —NH—, X³ is —CH₂—,X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)NR³—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —NH—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —NH—. X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —CH₂—, X² is —NH—, X³ is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—and X² is —O—. In one or more embodiments, X¹ is —CH₂—, X² is —O—, andX³ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is —O—, X³ is—CH₂— and X⁴ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—O—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —CH₂—. In one or moreembodiments, X¹ is —CH₂—, X² is —O—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—O—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —O—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —O—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —O—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—O—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In oneor more embodiments, X¹ is —CH₂—, X² is —O—, X⁴ is —CH₂—, X⁵ is —CH₂—,X⁶ is —CH₂—, m is 0 and n is 2. In one or more embodiments, X¹ is —CH₂—,X² is —O—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —O—, X⁴ is —CH₂—, X⁵ is—C(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In any of the above-embodiments,L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —O—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —O—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —O—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—O—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In one or more embodiments, X¹ is —CH₂—, X² is —O—, X³ is —CH₂—,X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —O—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —O—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —CH₂—, X² is —O—, X³ is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—and X₂ is —C(O)—. In one or more embodiments, X¹ is —CH₂—, X₂ is —C(O)—,and X³ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X₂ is —C(O)—,X³ is —CH₂— and X⁴ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X₂is —C(O)—, X³ is —CH₂—, X⁴ is —CH₂— and X¹ is —CH₂—. In one or moreembodiments, X¹ is —CH₂—, X₂ is —C(O)—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X₂ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X₂ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X₂ is —C(O)—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X₂ is —C(O)—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X₂ is—C(O)—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. Inone or more embodiments, X¹ is —CH₂—, X₂ is —C(O)—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one or more embodiments, X¹ is—CH₂—, X₂ is —C(O)—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 andn is 2. In one or more embodiments, X¹ is —CH₂—, X₂ is —C(O)—, X⁴ is—CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X₂ is —C(O)—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X₂ is —C(O)—, X³ is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X₂ is —C(O)—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is—CH₂—, X₂ is —C(O)—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X₂ is—C(O)—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 andn is 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X₂ is —C(O)—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X₂ is —C(O)—, X³is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X₂ is —C(O)—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—and X² is —S(O)₂—. In one or more embodiments, X¹ is —CH₂—, X² is—S(O)₂—, and X³ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X₂ is—S(O)₂—, X³ is —CH₂— and X⁴ is —CH₂—. In one or more embodiments, X¹ is—CH₂—, X² is —S(O)₂—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —CH₂—. In oneor more embodiments, X¹ is —CH₂—, X² is —S(O)₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is—CH₂—, X² is —S(O)₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0.In one or more embodiments, X¹ is —CH₂—, X² is —S(O)₂—, X⁴ is —CH₂—, X⁵is —CH₂—, m is 0 and n is 0. In one or more embodiments, X¹ is —CH₂—, X²is —S(O)₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. Inone or more embodiments, X¹ is —CH₂—, X² is —S(O)₂—, X⁴ is —C(O)—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is—CH₂—, X² is —S(O)₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 andn is 1. In one or more embodiments, X¹ is —CH₂—, X₂ is —S(O)—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one or moreembodiments, X¹ is —CH₂—, X² is —S(O)₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶is —CH₂—, m is 0 and n is 2. In one or more embodiments, X¹ is —CH₂—, X²is —S(O)₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 2.In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—,—S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or—C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —S(O)₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —S(O)₂—, X³ is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —S(O)₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is—CH₂—, X² is —S(O)₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—S(O)₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 andn is 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —S(O)₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —S(O)₂—, X³is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —S(O)₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—and X² is —S(O)—. In one or more embodiments, X¹ is —CH₂—, X² is —S(O)—,and X³ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is —S(O)—,X³ is —CH₂— and X⁴ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X²is —S(O)—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —CH₂—. In one or moreembodiments, X¹ is —CH₂—, X² is —S(O)—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—S(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —S(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —S(O)—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —S(O)—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—S(O)—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. Inone or more embodiments, X¹ is —CH₂—, X² is —S(O)—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one or more embodiments, X¹ is—CH₂—, X² is —S(O)—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 andn is 2. In one or more embodiments, X¹ is —CH₂—, X² is —S(O)—, X⁴ is—CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —S(O)—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —S(O)—, X³ is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —S(O)—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is—CH₂—, X² is —S(O)—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—S(O)—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 andn is 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —S(O)—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —S(O)—, X³is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —S(O)—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—and X² is —S—. In one or more embodiments, X¹ is —CH₂—, X² is —S—, andX³ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X₂ is —S—, X³ is—CH₂— and X⁴ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—S—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —CH₂—. In one or moreembodiments, X¹ is —CH₂—, X² is —S—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—S—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —S—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —S—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —S—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—S—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In oneor more embodiments, X¹ is —CH₂—, X² is —S—, X⁴ is —CH₂—, X⁵ is —CH₂—,X⁶ is —CH₂—, m is 0 and n is 2. In one or more embodiments, X¹ is —CH₂—,X² is —S—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —S—, X⁴ is —CH₂—, X⁵ is—C(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In any of the above-embodiments,L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —S—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —S—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —S—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—S—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In one or more embodiments, X¹ is —CH₂—, X² is —S—, X³ is —CH₂—,X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X²is —S—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —S—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —CH₂—, X² is —S—, X³ is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, and X³ is —NH—. In one or more embodiments, X¹ is —CH₂—, X²is —CH₂—, X³ is —NH— and X⁴ is —CH₂—. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X³ is —NH—, X⁴ is —CH₂— and X⁵ is —CH₂—. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —NH—, X⁴ is —CH₂—, X⁵is —CH₂— and X⁶ is —CH₂—. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹is —CH₂—,X² is —CH₂—, X³ is —NH—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —NH—,X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —NH—, X⁴ is —CH₂—, X₅ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —NH—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, is X² is—CH₂—, X³ is —NH—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1 and nis 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —NH—,X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, is —CH₂—, X²is —CH₂—, and X³ is —O—. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —O— and X⁴ is —CH₂—. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X³ is —O—, X⁴ is —CH₂— and X⁵ is —CH₂—. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —O—, X⁴ is —CH₂—, X⁵is —CH₂— and X⁶ is —CH₂—. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —O—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —O—,X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —O—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —O—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —O—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—O—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any ofthe above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, is —CH₂—, X²is —CH₂—, and X³ is —S—. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —S— and X⁴ is —CH₂—. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X³ is —S—, X⁴ is —CH₂— and X⁵ is —CH₂—. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —S—, X⁴ is —CH₂—, X⁵is —CH₂— and X⁶ is —CH₂—. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —S—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —S—,X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —S—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —S—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —S—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—S—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any ofthe above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, and X³ is —C(O)—. In one or more embodiments, X¹ is —CH₂—,X² is —CH₂—, X³ is —C(O)— and X⁴ is —CH₂—. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂— and X⁵ is —CH₂—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is—CH₂—, X⁵ is —CH₂— and X⁶ is —CH₂—. In any of the above-embodiments, Lis a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —C(O)—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In any of the above-embodiments,L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is1 and n is 2.. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR —, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, and X³ is —S(O)₂—. In one or more embodiments, X¹ is —CH₂—,X² is —CH₂—, X³ is —S(O)₂— and X⁴ is —CH₂—. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —S(O)₂—, X⁴ is —CH₂— and X⁵ is —CH₂—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —S(O)₂—, X⁴ is—CH₂—, X⁵ is —CH₂— and X⁶ is —CH₂—. In any of the above-embodiments, Lis a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —S(O)₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—S(O)₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —S(O)₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X³ is —S(O)₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —S(O)₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³is —S(O)₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —S(O)₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, and X³ is —S(O)—. In one or more embodiments, X¹ is —CH₂—,X² is —CH₂—, X³ is —S(O)— and X⁴ is —CH₂—. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —S(O)—, X⁴ is —CH₂— and X⁵ is —CH₂—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —S(O)—, X⁴ is—CH₂—, X⁵ is —CH₂— and X⁶ is —CH₂—. In any of the above-embodiments, Lis a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —S(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—S(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —S(O)—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is—CH₂—, X₂ is —CH₂—, X³ is —S(O)—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —S(O)—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³is —S(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —S(O)—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂— and X⁴ is —NH—. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —NH— and X⁵ is —CH₂—. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —NH—,X⁵ is —CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X²is —CH₂—, X⁴ is —NH—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —NH—, X⁵ is —CH₂—, mis 0 and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—,X⁴ is —NH—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —NH—, X⁵ is —C(O)—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —NH—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —NH—, X⁵ is —C(O)—,X⁶ is —CH₂—, m is 0 and n is 2. In any of the above-embodiments, L is abond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —NH—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —NH—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —NH—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —C(O)—, X⁴ is —NH—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —NH—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —NH—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —NH—,X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R³)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂— and X⁴ is —O—. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —O— and X⁵ is —CH₂—. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —O—, X⁵is —CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —O—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —O—, X⁵ is —CH₂—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—O—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —O—, X⁵ is —C(O)—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —O—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —O—, X⁵ is —C(O)—, X⁶is —CH₂—, m is 0 and n is 2. In any of the above-embodiments, L is abond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —O—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —O—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —O—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —C(O)—, X⁴ is —O—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —O—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —O—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —O—,X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, is —CH₂—, X²is —CH₂—, X³ is —CH₂— and X⁴ is —S—. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —S— and X⁵ is —CH₂—. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —S—, X⁵is —CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —S—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —S—, X⁵ is —CH₂—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—S—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —, —S—, X⁵ is —C(O)—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —S—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —S—, X⁵ is —C(O)—, X⁶is —CH₂—, m is 0 and n is 2. In any of the above-embodiments, L is abond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —S—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —S—, X⁵ is —CH₂—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —S—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —C(O)—, X⁴ is —S—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —S—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —S—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In oneor more embodiments, X¹ —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —S—, X⁵is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂— and X⁴ is —C(O)—. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)— and X⁵ is —CH₂—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—C(O)—, X⁵ is —CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X₅ is —CH₂—, X⁶ is —CH₂— and m is 0.In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X₅is —CH₂—, m is 0 and n is 0. In one or more embodiments, X¹ is —CH₂—, X²is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is—C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X₅ is —C(O)—, X⁶ is —CH₂—, m is 0and n is 2. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —C(O)—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —C(O)—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In any of the above-embodiments,L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³is —C(O)—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—C(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂— and X⁴ is —S(O)₂—. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —S(O)₂— and X⁵ is —CH₂—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—S(O)₂—, X⁵ is —CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X⁴ is —S(O)₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0.In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —S(O)₂—, X⁵is —CH₂—, m is 0 and n is 0. In one or more embodiments, X¹ is —CH₂—, X²is —CH₂—, X⁴ is S(O)₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —S(O)₂—, X⁵ is—C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X⁴ is —S(O)₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—S(O)₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —S(O)₂—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —S(O)₂—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —S(O)₂—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X³ is —(C(O)—, X⁴ is —S(O)₂—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —CH₂—, X⁴ is —S(O)₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 andn is 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —S(O)₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³is —C(O)—, X⁴ is —S(O)₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2.In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—S(O)₂—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂— and X⁴ is —S(O)—. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —S(O)— and X⁵ is —CH₂—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—S(O)—, X⁵ is —CH₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X⁴ is —S(O)—, X⁵ is —CH₂—, X⁶ is —CH₂— and m is 0.In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —S(O)—, X⁵is —CH₂—, m is 0 and n is 0. In one or more embodiments, X¹ is —CH₂—, X²is —CH₂—, X⁴ is —S(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0 and n is 1. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —S(O)—, X⁵ is—C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X⁴ is —S(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 0and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—S(O)—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, is —CH₂—, X²is —CH₂—, X³ is —CH₂—, X⁴ is —S(O)—, X⁵ is —CH₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —S(O)—, X⁵ is —CH₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —S(O)—, X⁵ is—CH₂—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —S(O)—, X⁵ is —CH₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —CH₂—, X⁴ is —S(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and nis 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —S(O)—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³is —C(O)—, X⁴ is —S(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—S(O)—, X⁵ is —CH₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —NH—. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—NH— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —NH—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —NH—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—CH₂—, X⁵ is —NH—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —NH—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —NH—, X⁶ is —CH₂—, m is 0 and n is 2. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —NH—,X⁶ is —CH₂—, m is 0 and n is 2. In any of the above-embodiments, L is abond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —NH—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —NH—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —NH—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —NH—, X⁶ is —CH₂—, m is 1 and nis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —C(O)—, X⁵ is —NH—, X⁶ is —CH₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —NH—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—CH₂—, X⁴ is —CH₂—, X⁵ is —NH—, X⁶ is —CH₂—, m is 1 and n is 2. In anyof the above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—,—S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or—C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —O—. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—O— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —O—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —O—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—CH₂—, X⁵ is —O—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —O—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —O—, X⁶ is —CH₂—, m is 0 and n is 2. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X4 is —C(O)—, X⁵ is , X⁶ is—CH₂—, m is 0 and n is 2. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —O—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —O—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —O—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —O—, X⁶ is —CH₂—, m is 1 and nis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —C(O)—, X⁵ is —O—, X⁶ is —CH₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —O—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—CH₂—, X⁴ is —CH₂—, X⁵ is —O—, X⁶ is —CH₂—, m is 1 and n is 2. In any ofthe above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —S—. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—S— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —S—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —S—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—CH₂—, X⁵ is —S—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —S—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —S—, X⁶ is —CH₂—, m is 0 and n is 2. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —S—, X⁶is —CH₂—, m is 0 and n is 2. In any of the above-embodiments, L is abond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —S—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —S—, m is 1 and n is 0. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —S—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —S—, X⁶ is —CH₂—, m is 1 and nis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —C(O)—, X⁵ is —S—, X⁶ is —CH₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —S—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—CH₂—, X⁴ is —CH₂—, X⁵ is —S—, X⁶ is —CH₂—, m is 1 and n is 2. In any ofthe above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —C(O)—. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—C(O)— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—C(O)—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —C(O)—, X⁶ is—CH₂—, m is 0 and n is 2. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —C(O)13 , m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—C(O)—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is 1 andn is 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —CH₂—, m is1 and n is 2. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —S(O)₂—. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—S(O)₂— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —S(O)₂—, X⁶ is —CH₂— and m is 0. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —S(O)₂—,m is 0 and n is 0. In one or more embodiments, X¹ is X² is —CH₂—, X⁴ is—CH₂—, X⁵ is —S(O)₂—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —S(O)₂—, X⁶is —CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X²is —CH₂—, X⁴ is —CH₂—, X⁵ is —S(O)₂—, X⁶ is —CH₂—, m is 0 and n is 1. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—S(O)₂—, X⁶ is —CH₂—, m is 0 and n is 2. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —S(O)₂—, X⁶ is —CH₂—, m is 0and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—CH₂—, X⁵ is —S(O)₂—, X⁶ is —CH₂—, m is 0 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —S(O)₂—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X¹ is —S(O)₂—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—S(O)₂—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —S(O)₂—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —S(O)₂—, X⁶ is —CH₂—, m is 1 andn is 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —S(O)₂—, X⁶ is —CH₂—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³is —C(O)—, X⁴ is —CH₂—, X⁵ is —S(O)₂—, X⁶ is —CH₂—, m is 1 and n is 2.In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —S(O)₂—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² —CH₂—, X³ is —CH₂—, X⁴ is —CH₂— and X⁵ is —S(O)—. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—S(O)— and X⁶ is —CH₂—. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —S(O)—, X⁶ is —CH₂— and m is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —S(O)—, m is 0and n is 0. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—CH₂—, X⁵ is —S(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—X⁴ is —C(O)—, X⁵ is —S(O)—, X⁶ is—CH₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —S(O)—, X⁶ is —CH₂—, m is 0 and n is 1. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—S(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —S(O)—, X⁶ is —CH₂—, m is 0and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—CH₂—, X⁵ is —S(O)—, X⁶ is —CH₂—, m is 0 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —S(O)—, X⁶ is —CH₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —S(O)—, m is 1 and n is 0. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is—S(O)—, X⁶ is —CH₂—, m is 1 and n is 1. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is —S(O)—, X⁶ is—CH₂—, m is 1 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —S(O)—, X⁶ is —CH₂—, m is 1 andn is 1. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —S(O)—, X⁶ is —CH₂—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —S(O)—, X⁶ is —CH₂—, m is 1 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —S(O)—, X⁶ is —CH₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is —NH—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —NH— and m is 0. In one or more embodiments, X¹ is —CH₂—,X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —NH—, m is 0 and n is 1. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is—CH₂—, X⁶ is —NH—, m is 0 and n is 1. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —NH—, m is 0 and nis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —NH—, m is 0 and n is 2. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —NH—, m is 0and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—CH₂—, X⁵ is —C(O)—, X⁶ is —NH—, m is 0 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR —, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —NH— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —NH—, m is 1 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —NH—, m is 1 and n is 1. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —NH—,m is 1 and n is 1. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —NH—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —NH—, m is 1 and n is 2. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —NH—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is —O—. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—,X⁶ is —O— and m is 0. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —O—, m is 0 and n is 1. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—,X⁶ is —O—, is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X²is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —O—, m is 0 and n is 1. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —O—, m is 0 and n is 2. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —O—, m is 0 and nis 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is X⁵ is—C(O)—, X⁶ is —O—, m is 0 and n is 2. In any of the above-embodiments, Lis a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —O— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —O—, m is 1 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —O—, m is 1 and n is 1. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —O—, mis 1 and n is 1. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —O—, m is 1and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —O—, m is 1 and n is 2. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —O—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is —C(O)—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —C(O)— and m is 0. In one or more embodiments, X¹ is —CH₂—,X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —C(O)—, m is 0 and n is 1.In one or more embodiments, X¹ is —CH₂—, X² —CH₂—, X⁴ is —C(O)—, X⁵ is—CH₂—, X⁶ is —C(O)—, m is 0 and n is 1. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —C(O)—, m is 0and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —C(O)—, m is 0 and n is 2. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ mis 0 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—,X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —C(O)—, m is 0 and n is 2. In any ofthe above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —C(O)— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —C(O)—, m is 1 and n is 1. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —C(O)—, m is 1 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is—CH₂—, X⁶ is —C(O)—, m is 1 and n is 1. In any of the above-embodiments,L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —C(O)—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —C(O)—, m is 1 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —C(O)—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is —S(O)₂—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —S(O)₂— and m is 0. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)₂—, m is 0 andn is 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ —C(O)—,X⁵is —CH₂—, X⁶ is —S(O)₂—, m is 0 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is—S(O)₂—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X²is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)₂—, m is 0 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is—CH₂—, X⁶ is —S(O)₂—, m is 0 and n is 2. In one or more embodiments, X¹is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —S(O)₂—, m is 0and n is 2. In any of the above-embodiments, L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)₂— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)₂—, m is 1 and n is 1. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —S(O)₂—, m is 1 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is—CH₂—, X⁶ is —S(O)₂—, m is 1 and n is 1. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —S(O)₂—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)₂—, m is 1 and n is 2.In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X6 is —S(O)₂—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is —S(O)—. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —S(O)— and m is 0. In one or more embodiments, X¹ is —CH₂—,X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)—, m is 0 and n is 1.In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵is —CH₂—, X⁶ is —S(O)—, m is 0 and n is 1. In one or more embodiments,X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —S(O)—, m is0 and n is 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴is —CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)—, m is 0 and n is 2. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is—S(O)—, m is 0 and n is 2. In one or more embodiments, X¹ is —CH₂—, X²is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —S(O)—, m is 0 and n is 2. Inany of the above-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—,—S(O)₂—, ——S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or—C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)—, m is 1 and n is 1. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —S(O)—, m is 1 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is—CH₂—, X⁶ is —S(O)—, m is 1 and n is 1. In any of the above-embodiments,L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —S(O)—, m is1 and n is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³is —C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)—, m is 1 and n is 2. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is—CH₂—, X⁵ is —CH₂—, X⁶ is —S(O)—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂— and X⁶ is —S—. In oneor more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—,X⁶ is —S— and m is 0. In one or more embodiments, X¹ is —CH₂—, X² is—CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S—, m is 0 and n is 1. In one ormore embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—,X⁶ is —S—, m is 0 and n is 1. In one or more embodiments, X¹ is —CH₂—,X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —C(O)—, X⁶ is —S—, m is 0 and n is 1. Inone or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —S—, m is 0 and n is 2. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —S—, m is 0 and nis 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—,X⁵ is —C(O)—, X⁶ is —S—, m is 0 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂—, X² is —CH₂—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S— and mis 1. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —CH₂—,X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S—, m is 1 and n is 1. In one or moreembodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is —C(O)—, X⁴ is —CH₂—, X⁵ is—CH₂—, X⁶ is —S—, m is 1 and n is 1. In one or more embodiments, X¹ is—CH₂—, X² is —CH₂—, X³ is —CH₂—, X⁴ is —C(O)—, X⁵ is —CH₂—, X⁶ is —S—, mis 1 and n is 1. In any of the above-embodiments, L is a bond,—(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—,—C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, X¹ is —CH₂—,X² is —CH₂, X³ is —CH₂—, X⁴ is —CH₂, X⁵ is —C(O)—, X⁶ is —S—, m is 1 andn is 2. In one or more embodiments, X¹ is —CH₂—, X² is —CH₂—, X³ is—C(O)—, X⁴ is —CH₂—, X⁵ is —CH₂—, X⁶ is —S—, m is 1 and n is 2. In oneor more embodiments, X¹ is —CH₂, X² is —CH₂—, X³ is —CH₂—, X⁴ is —CH₂—,X⁵ is —CH₂—, X⁶ is —S—, m is 1 and n is 2. In any of theabove-embodiments, L is a bond, —(CR¹R²)_(p)—, —C(O)NR³—, —S(O)₂—,—S(O)₂NR³—, —S(O)—, —S(O)NR³, —C(O)(CR¹R²)_(p)O—, or —C(O)(CR¹R²)_(p)—.

In one or more embodiments of the compounds of Formula IB, the compoundis of the formula IB-1, IB-2, IB-3, IB-4, IB-5, IB-6, IB-7, or IB-8:

In one or more embodiments, a compound of Formula I can be:

-   (R)-N-hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-1);-   (S)-N-hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-2);-   (R)-N-hydroxy-1′-isopropyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-3);-   (S)-N-hydroxy-1′-isopropyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-4);-   (R)-1′-ethyl-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-5);-   (S)-1′-ethyl-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-6);-   (R)-N-hydroxy-1′-isobutyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-7);-   (S)-N-hydroxy-1′-isobutyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-8);-   (R)-N-hydroxy-1′-(2-methylbenzyl)-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-9);-   (S)-N-hydroxy-1′-(2-methylbenzyl)-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-10);-   (R)-1′-benzyl-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-11);-   (S)-1′-benzyl-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-12);-   (R)-N-hydroxy-2′-oxo-1′-phenyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-13);-   (S)-N-hydroxy-2′-oxo-1′-phenyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-14);-   (R)-1′-(4-fluorophenyl)-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-15);-   (S)-1′-(4-fluorophenyl)-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-16);-   (R)-N-hydroxy-2′-oxo-1′-(pyridin-3-yl)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-17);-   (S)-N-hydroxy-2′-oxo-1′-(pyridin-3-yl)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-18);-   (R)-N-hydroxy-2′-oxo-1′-(pyridin-2-yl)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-19);-   (S)-N-hydroxy-2′-oxo-1′-(pyridin-2-yl)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-20);-   (R)-N-hydroxy-2′-oxo-1′-(pyridin-4-yl)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-21);-   (S)-N-hydroxy-2′-oxo-1′-(pyridin-4-yl)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-22);-   (R)-N-hydroxy-2′-oxo-1′-(pyridin-3-ylmethyl)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-23);-   (R)-N-hydroxy-1′-methyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-24);-   (S)-N-hydroxy-1′-methyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-25);-   (R)-1′-benzyl-N-hydroxy-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-26);-   (S)-1′-benzyl-N-hydroxy-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-27);-   (R)-1′-acetyl-N-hydroxy-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-28);-   (S)-1′-acetyl-N-hydroxy-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-29);-   (R)-1′-benzoyl-N-hydroxy-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-30);-   (S)-1′-benzoyl-N-hydroxy-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-31);-   (R)-N-hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide    (I-32);-   (S)-N-hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide    (I-33);-   (R)-1′-benzyl-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide    (I-34);-   (S)-1′-benzyl-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide    (I-35);-   (R)-N-hydroxy-2′-oxo-1′-phenyl-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide    (I-36); or-   (S)-N-hydroxy-2′-oxo-1′-phenyl-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide    (I-37).

In one or more embodiments, a compounds of Formula I can be:

-   N-hydroxy-1′-methyl-5′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide    (I-38);-   N-hydroxy-1′-methyl-6′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide    (I-39);-   N-hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-5-carboxamide    (I-40);-   N-hydroxy-1′-methyl-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide    (I-41);-   N-hydroxy-1′-methyl-1,3-dihydrospiro[indene-2,4′-piperidine]-5-carboxamide    (I-42);-   N-hydroxy-1′-methyl-3H-spiro[benzofuran-2,4′-piperidine]-6-carboxamide    (I-43); or-   N-hydroxy-1′-methyl-3H-spiro[benzofuran-2,4′-piperidine]-6-carboxamide    (I-44).

In some embodiments of the invention, the compounds of Formula I areenantiomers. In some embodiments the compounds are the (S)-enantiomer.In other embodiments the compounds are the (R)-enantiomer. In yet otherembodiments, the compounds of Formula I may be (+) or (−) enantiomers.As used herein, a chemical structure that is labelled as “R/S” indicatesthat the structure represents one enantiomer, the stereochemistry ofwhich is not defined.

It should be understood that all isomeric forms are included within thepresent invention, including mixtures thereof. If the compound containsa double bond, the substituent may be in the E or Z configuration. Ifthe compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans- configuration. All tautomericforms are also intended to be included.

Methods of Synthesizing the Disclosed Compounds

The compounds of the present invention may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the schemes given below.

The compounds of Formula I may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes and examples. In the schemes described below, it is wellunderstood that protecting groups for sensitive or reactive groups areemployed where necessary in accordance with general principles orchemistry. Protecting groups are manipulated according to standardmethods of organic synthesis (T. W. Greene and P. G. M. Wuts,“Protective Groups in Organic Synthesis”, Third edition, Wiley, New York1999). These groups are removed at a convenient stage of the compoundsynthesis using methods that are readily apparent to those skilled inthe art. The selection processes, as well as the reaction conditions andorder of their execution, shall be consistent with the preparation ofcompounds of Formula I.

Those skilled in the art will recognize if a stereocenter exists in thecompounds of Formula I. Accordingly, the present invention includes bothpossible stereoisomers (unless specified in the synthesis) and includesnot only racemic compounds but the individual enantiomers and/ordiastereomers as well. When a compound is desired as a single enantiomeror diastereomer, it may be obtained by stereospecific synthesis or byresolution of the final product or any convenient intermediate.Resolution of the final product, an intermediate, or a starting materialmay be affected by any suitable method known in the art. See, forexample, “Stereochemistry of Organic Compounds” by E. L. Eliel, S. H.Wilen, and L. N. Mander (Wiley-Interscience, 1994).

Preparation of Compounds

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

The compounds of the present invention can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the Formula I (e.g., Formula IA-9 and IA-10)can be synthesized using the methods described below, together withsynthetic methods known in the art of synthetic organic chemistry, orvariations thereon as appreciated by those skilled in the art. Thesemethods include but are not limited to those methods described below.

wherein L and R are defined as in Formula (I).

The general way of preparing target molecules of Formula (IA-9) by usingintermediates 1a, 1b, 1c, 1d, 1e, 1f, 1g, and 1h is outlined inScheme 1. Carbonylation of 5-bromo-2,3-dihydro-1H-inden-1-one (1a) inthe presence of a metal catalyst, e.g.,[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl₂), carobon monoxide, and a base, e.g., triethylamine (Et₃N),provides ester 1b. Deprotonation of 1b using a strong base, e.g., sodiumhydride (NaH), in the presence of dimethyl carbonate affordsIntermediate 1c, which can be alkylated by treatment with a halo-nitrilein the presence of a base to provide Intermediates 1d. Reduction, forexample, with hydrogen gas in the presence of platinum (IV) oxide(PtO₂), acetic acid, and methanol, can provide amino-alcoholIntermediates 1e. Spiro-lactams 1f can be obtained by treatment of 1ewith ammonia (NH₃) in methanol. Dehydroxylation of 1f by conversion tothe silyl ether can be accomplished by treatment with triethylsilane andTFA to provide Intermediates 1g. Addition of the R-L moiety can beachieved via standard methods of alkylation or arylation. For example,alkylation of 1g, with an alkyl halide in the presence of a base, e.g.,sodium hydride, can provide compounds of Intermediates 1h.Alternatively, arylation of 1g with an aryl boronic acid in the presenceof a metal catalyst, e.g., copper (II) acetate (Cu(OAc)₂), and a base,e.g., Et₃N, can also provide compounds of intermediates 1h. Treatment of1h with hydroxylamine and a base, e.g., sodium hydroxide, providescompounds of Formula (IA-9).

wherein L and R are defined as in Formula (I).

The general way of preparing target molecules of Formula (IA-10) byusing intermediates 1g, 1i, 1j, and 1k is outlined in Scheme 2.Spiro-amines 1j can be obtained via reduction of thiolactam 1i bytreatment of 1g with2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane(Lawesson reagent), followed by sodium borohydride (NaBH₄) in thepresence of Nickel (II) chloride hexahydrate (NiCl₂.6H₂O). Addition ofthe R-L moiety can be achieved via standard methods of alkylation,acylation, acylation, urea formation, or sulfonation. Treatment of 1kwith hydroxylamine and a base, e.g., sodium hydroxide, providescompounds of Formula (IA-10).

Methods of Using the Diseiosed Compounds

Another aspect of the invention relates to a method of treating adisease associated with HDAC6 modulation in a subject in need thereof.The method involves administering to a patient in need of treatment fordiseases or disorders associated with HDAC6 modulation an effectiveamount of a compound of Formula I. In an embodiment, the disease can be,but is not limited to, cancer, neurodegenerative disease,neurodevelopmental disease, inflammatory or autoimmune disease,infection, metabolic disease, hematologic disease, transplant rejection,or cardiovascular disease.

Another aspect of the invention is directed to a method of inhibitingHDAC6. The method involves administering to a patient in need thereof aneffective amount of Formula I.

The present invention relates to compositions capable of modulating theactivity of (e.g., inhibiting) HDACs, and in particular HDAC6. Thepresent invention also relates to the therapeutic use of such compounds.

One therapeutic use of the compounds of the present invention is totreat proliferative diseases or disorders such as cancer. Cancer can beunderstood as abnormal or unregulated cell growth within a patient andcan include but is not limited to lung cancer, ovarian cancer, breastcancer, prostate cancer, pancreatic cancer, hepatocellular cancer, renalcancer and leukemias such as acute myeloid leukemia and acutelymphoblastic leukemia. Additional cancer types include T-cell lymphoma(e.g., cutaneous T-cell lymphoma, peripheral T-cell lymphoma), Hodgkinlymphoma, melanoma and multiple myeloma. In other embodiments, treatingproliferative diseases or disorders can include any cancer where thereis evidence of an increase in Treg/effector T cell ratio or in anabsolute Treg number, either in the periphery or in the tumormicroenvironment or tertiary lymphoid structures, or increasedexpression of T cell tolerance-related genes. Such proliferativediseases or disorders can include but are not limited to: any Krasmutant carrying tumor (Zdanov et at, Mutant KRAS conversion ofconventional T cells into regulatory T cells. Cancer Immunol. Res. Feb.15, 2016, DOI: 10.1158/2326-6066.CIR-15-0241); renal cell carcinoma;lung carcinoma; cervical cancer; prostate cancer; ovarian cancer; headand neck cancer; lymphoma; colorectal cancer, non-small cell lungcarcinoma; breast cancers (Gobert, M. et al., (2009) Cancer Res. 69,2000-2009); and bladder cancer.

One therapeutic use of the compounds of the present disclosure is totreat neurological diseases or disorders or neurodegeneration.Neurological disorders are understood as disorders of the nervous system(e.g., the brain and spinal cord). Neurological disorders orneurodegenerative diseases can include but are not limited to epilepsy,attention deficit disorder (ADD), Alzheimer's disease, Parkinson'sDisease, Huntington's Disease, amyotrophic lateral sclerosis, spinalmuscular atrophy, essential tremor, central nervous system trauma causedby tissue injury, oxidative stress-induced neuronal or axomaldegeneration, and multiple sclerosis.

Another therapeutic use of the compounds of the present disclosure is totreat neurodevelopmental disorders. Neurodevelopmental disorders caninclude, but are not limited to, Rett syndrome, intellectual disability,intellectual and developmental disability, autism spectrum disorder,fetal alcohol syndrome, developmental coordination disorder, stereotypicmovement disorder, Tourette syndrome, cerebral palsy, fragile Xsyndrome, attention deficit hyperactivity disorder, and Mendelsohnn'ssyndrome.

Another therapeutic use of the compounds of the present invention isalso to treat inflammatory diseases or disorders. Inflammation can beunderstood as a host's response to an initial injury or infection.Symptoms of inflammation can include but are not limited to redness,swelling, pain, heat and loss of function. Inflammation may be caused bythe upregulation of pro-inflammatory cytokines such as IL-1β, andincreased expression of the FOXP3 transcription factor. In someembodiments, the inflammatory diseases include fibrosis or fibroticdiseases. Types of fibrotic diseases include but are not limited to lungfibrosis or pulmonary fibrosis, Liver fibrosis; Heart fibrosis;Mediastinal fibrosis; Retroperitoneal cavity fibrosis; Bone marrowfibrosis; Skin fibrosis; and Scieroderma or systemic sclerosis.

Another therapeutic use of the compounds of the present invention isalso to treat autoimmune diseases or disorders. Autoimmune disorders areunderstood as disorders wherein a host's own immune system responds totissues and substances occurring naturally in the host's body.Autoimmune diseases can include but are not limited to rheumatoidarthritis, Crohn's disease, type-1 diabetes, systemic juvenileidiopathic arthritis; inflammatory bowel disease; allografttransplantation; eczema, psoriasis, idiopathic thrombocytopenic purpra,autoimmune thromb ocytopeni a, acquired immune thrombocytopenia,autoimmune neutropenia,autoi mmune hemolyitic anemia, parvovirusB19-associated red cell aplasia, acquired antifactor VIII autoimmunity,acquired von Willebrand disease, monoclonal gammopathy, aplastic anemia,pure red cell aplasia, Diamond-Blackfan anemia, hemolytic disease of thenewborn, immune mediated-refractoriness to platelet transfusion,hemolytic uremic syndrome, Evan's syndrome, Guillain-Barre syndrome,chronic demyelinating polyradicul oneuropathy, paraproteinemic IgMdemyelinating polyneuropathy, Lamber-Eaton myasthenic syndrome,myasthenia gravis, multifocal motor neuropathy, stiff man syndrome,paraneoplastic encephalomyelitis, sensory neuropathy with anti-Huantibodies, myelitis, autoimmune diabetic neuropathy, acute idiopathicneuropathy, toxic epidermal necrolysis, gangrene, granuloma, pemphigusvulgaris, bullous pemphigoid, vitiligo, scleroderma, atomic dermatitis,systemic and diffuse sclerosis, primary biliary cirrhosis, Celiacdisease, dermatitis herpetiformis, cryptogenic cirrhosis, reactivearthritis, Hashimoto's thryroditis, Wegner's granulomoatosis,micropolyarterits, Churg-Strauss syndrome Type I and Type II autoimmunepolyglandular syndromes, linear IgA disease, epidermolysis bullosaacquisita, erythema nodosa, pemphigoid gestationis, cicatricialpemphigoid, mixed essential cryoglobulinemia, chronic bullous disease ofchildhood, Goodpasture's syndrome, sclerosis cholangitis, ankylosingspondylitis, Bechet's syndrome temporal arteritis, Takayasu's arteritis,autoimmune urticaria, and Kawasaki's disease.

In some embodiments, the cancer to be treated is melanoma, cutaneousT-cell lymphoma, peripheral T-cell lymphoma, Hodgkin lymphoma, multiplemyeloma, leukemia, lung, ovarian, breast, prostate, pancreatic,hepatocellular or renal cancer. In some embodiments, the cancer to betreated is cutaneous T-cell lymphoma, peripheral T-cell lymphoma,multiple myeloma, lymphoma, leukemia, lung, ovarian, breast, prostate,pancreatic, hepatocellular or renal cancer. In other embodiments, theneurodegenerative disease to be treated is Alzheimer's Disease,Huntington's Disease, Parkinson's Disease, Amyotrophic LateralSclerosis, or spinal muscular atrophy. In other embodiments, theneurodevelopmental disorder to be treated is Rett syndrome. In yet otherembodiments, the inflammatory or autoimmune disease to be treated isrheumatoid arthritis, spondylitis arthritis, psoriatic arthritis,psoriasis, multiple sclerosis, systemic lupus erythematosus,inflammatory bowel diseases, graft versus host disease, transplantrejection or fibrotic disease.

Another therapeutic use of the compounds of the present invention isalso to treat and/or prevent allergy and unwanted immune responsesassociated with allergy. A non-limiting list of allergies and relatedconditions includes, pollen allergy (e.g. Japanese Cedar Pollen), moldallergy, food allergies (including, but not limited to peanut, tree nut,milk, soy, gluten, and egg allergies), animal allergies (e.g. allergiesto dogs, cats, rabbits), dust mite allergy, atopic dermatitis, allergicrhinitis, allergic otitis, allergic asthma, dry eye, ocular allergy,allergic urticaria, contact dermatitis, anaphalaxis, eosinophilicesophagitis.

Another therapeutic use of the compounds of the present invention isalso to treat infectious diseases or disorders. Infections or infectiousdiseases are caused by the invasion of a foreign pathogen. The infectionmay be caused by, for instance, a bacteria, a fungus, or virus.Bacterial infections include, but are not limited to streptococcusinfections, mycobacterial infections, bacillus infections, Salmonellainfections, Vibrio infections, spirochete infections, and Neisseriainfections. Viral infections include, but are not limited to herpesvirus infections, hepatitis virus infections, west mile virusinfections, flavivrus infections, influenza virus infections, rhinovirusinfections, papillomavirus infections, paromyxovirus infections,parainfluenza virus infections, and retrovirus infections. In particularembodiments, the compounds of the present invention are useful fortreating infections which result in an inflammatory cytokine burst.Nonlimiting examples of such infections include Ebola and othe viralhemorghagic fever-causing viruses, and Malaria.

Yet another therapeutic use of the compounds of the present invention isalso to treat metabolic diseases or disorders. Metabolic diseases can becharacterized as abnormalities in the way that a subject stores energy.Metabolic disorders can include but are not limited to metabolicsyndrome, diabetes, obesity, high blood pressure, non-alcoholic fattyliver disease and heart failure.

Yet another therapeutic use of the compounds of the present invention isalso to treat hematologic disorders. Hematologic diseases primarilyaffect the blood. Hematologic disorders can include but are not limitedto anemia, multiple myeloma, lymphoma, and leukemia.

Yet another therapeutic use of the compounds of the present invention isalso to prevent and/or treat transplant rejection. Tissues that aretransplanted include (but are not limited to) whole organs such askidney, liver, heart, lung; organ components such as skin grafts and thecornea of the eye; and cell suspensions such as bone marrow cells andcultures of cells selected and expanded from bone marrow or circulatingblood, and whole blood transfusions.

Yet another therapeutic use of the compounds of the present invention isalso to treat cardiovascular diseases or disorders. Cardiovasculardiseases affect the heart and blood vessels of a patient. Exemplaryconditions include but are not limited to cardiovascular stress,pressure overload, chronic ischemia, infarction-reperfusion injury,hypertension, Brain infarct after cerebral artery occlusion,atherosclerosis, peripheral artery disease, cardiac hypertrophy, cardiacarrhythmias, stroke, and heart failure.

Another therapeutic use of the compounds of the present invention is forpurging the reservoir of latently infected memory CD4+ T cells in HIV+patients (Matalon, et al., Mol Med. 2011; 17(5-6): 466-472), which ishereby incorporated by reference in its entirety.

The disclosed compound can be administered in effective amounts to treator prevent a disorder and/or prevent the development thereof insubjects.

Another aspect of the present disclosure relates to a compound ofFormula I, or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, for use in treating orpreventing a disease associated with HDAC6 modulation. In someembodiments, the disease is cancer, neurodegenerative disease,neurodevelopmental disorder, inflammatory or autoimmune disease,infection, metabolic disease, hematologic disease, transplant rejectionor cardiovascular disease. In some embodiments, the compound inhibits ahistone deacetylase. In another embodiment, the compound inhibits azinc-dependent histone deacetylase. In another embodiment, the compoundinhibits the HDAC6 isozyme zinc-dependent histone deacetylase.

In another aspect, the present disclosure relates to the use of acompound of Formula (I), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof, in the manufactureof a medicament for treating or preventing a disease associated withHDAC6 modulation. In some embodiments, the disease is cancer,neurodegenerative disease, neurodevelopmental disorder, inflammatory orautoimmune disease, infection, metabolic disease, hematologic disease,transplant rejection, or cardiovascular disease. In some embodiments,the compound inhibits a histone deacetylase. In another embodiment, thecompound inhibits a zinc-dependent histone deacetylase. In anotherembodiment, the compound inhibits the HDAC6 isozyme zinc-dependenthistone deacetylase.

In some embodiments, the cancer is melanoma, cutaneous T-cell lymphoma,peripheral T-cell lymphoma, Hodgkin lymphoma, multiple myeloma,leukemia, lung, ovarian, breast, prostate, pancreatic, hepatocellular orrenal cancer. In some embodiments, the cancer is cutaneous T-celllymphoma, peripheral T-cell lymphoma, multiple myeloma, lymphoma,leukemia, lung, ovarian, breast, prostate, pancreatic, hepatocellular orrenal cancer. In other embodiments, the neurodegenerative disease isAlzheimer's Disease, Huntington's Disease, Parkinson's Disease,Amyotrophic Lateral Sclerosis, or spinal muscular atrophy. In otherembodiments, the neurodevelopmental disorder is Rett syndrome. In yetother embodiments, the inflammatory or autoimmune disease is rheumatoidarthritis, spondylitis arthritis, psoriatic arthritis, psoriasis,multiple sclerosis, systemic lupus erythematosus, inflammatory boweldiseases, graft versus host disease, transplant rejection or fibroticdisease.

Administration of the disclosed compounds can be accomplished via anymode of administration for therapeutic agents. These modes includesystemic or local administration such as oral, nasal, parenteral,transdermal, subcutaneous, vaginal, buccal, rectal or topicaladministration modes.

Depending on the intended mode of administration, the disclosedcompositions can be in solid, semi-solid or liquid dosage form, such as,for example, injectables, tablets, suppositories, pills, time-releasecapsules, elixirs, tinctures, emulsions, syrups, powders, liquids,suspensions, or the like, sometimes in unit dosages and consistent withconventional pharmaceutical practices. Likewise, they can also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous or intramuscular form, and all using forms well known tothose skilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatincapsules comprising a compound of the disclosure and a pharmaceuticallyacceptable carrier, such as a) a diluent, e.g., purified water,triglyceride oils, such as hydrogenated or partially hydrogenatedvegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil,safflower oil, fish oils, such as EPA or DHA, or their esters ortriglycerides or mixtures thereof, omega-3 fatty acids or derivativesthereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,sodium, saccharin, glucose anchor glycine; b) a lubricant, e.g., silica,talcum, stearic acid, its magnesium or calcium salt, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and/or polyethylene glycol; for tablets also; c) abinder, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesiumcarbonate, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) adisintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthangum, algiic acid or its sodium salt, or effervescent mixtures; e)absorbent, colorant, flavorant and sweetener; f) an emulsifier ordispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g)an agent that enhances absorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, compositions can, for example, beprepared by dissolution, dispersion, etc. For example, the disclosedcompound is dissolved in or mixed with a pharmaceutically acceptablesolvent such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form an injectable isotonic solutionor suspension. Proteins such as albumin, chylomicron particles, or serumproteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also formulated as a suppository that canbe prepared from fatty emulsions or suspensions; using polyalkyleneglycols such as propylene glycol, as the carrier.

The disclosed compounds can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, containing cholesterol, steatyl amine orphosphatidylcholines. In some embodiments, a film of lipid components ishydrated with an aqueous solution of drug to a form lipid layerencapsulating the drug, as described in U.S. Pat. No. 5,262,564.

Disclosed compounds can also be delivered by the use of monoclonalantibodies as individual carriers to which the disclosed compounds arecoupled. The disclosed compounds can also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the disclosedcompounds can be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked oramphipathic block copolymers of hydrogels. In one embodiment, disclosedcompounds are not covalently bound to a polymer, e.g., a polycarboxylicacid polymer, or a polyacrylate.

Parental injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions or solid forms suitable for dissolving in liquid prior toinjection.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound of Formula I and a pharmaceutically acceptablecarrier. The pharmaceutically acceptable carrier can further include anexcipient, diluent, or surfactant.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 99%,from about 5% to about 90%, or from about 1% to about 20% of thedisclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular disclosed compoundemployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for theindicated effects, range from about 0.5 mg to about 5000 mg of thedisclosed compound as needed to treat the condition. Compositions for invivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150,250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosedcompound, or, in a range of from one amount to another amount in thelist of doses. In one embodiment, the compositions are in the form of atablet that can be scored.

Without wishing to be bound by any particular theory, the compounds ofthe present invention can inhibit HDACs such as HDAC6 by interactingwith the zinc (Zn²⁺) ion in the protein's active site via the hydroxamicacid group bound to the aromatic ring of the compound. The binding canprevent the zinc ion from interacting with its natural substrates, thusinhibiting the enzyme.

EXAMPLES

The disclosure is further illustrated by the following examples andsynthesis examples, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

The present invention includes a number of unique features andadvantages compared with other inhibitors of HDAC enzymes, in particularHDAC6. For instance, the present invention features a unique class ofsmall molecule therapeutic agents of Formula I.

Definitions used in the following examples and elsewhere herein are:

-   -   AcOH Acetic Acid    -   CH₂Cl₂ Methylene chloride, Dichloromethane    -   CH₃CN Acetonitrile    -   CH₃I Iodomethane    -   CO (g) Carbon monoxide (gas)    -   CO₂ Carbon dioxide    -   Cs₂CO₃ Cesium carbonate    -   Cu(OAc)₂ Copper (II) acetate    -   DMA Dimethylacetamide    -   DMF N,N-Dimethylformamide    -   DMSO Dimethylsulfoxide    -   Et₃N Triethylamine    -   EtOAc Ethyl acetate    -   EtOH Ethanol    -   h hours    -   H₂ (g) Hydrogen (gas)    -   H₂O Water    -   HCl Hydrochloric acid    -   MeOH Methanol    -   min minutes    -   Na₂SO₄ Sodium sulfate    -   NaBH₃CN Sodium cyanoborohydride    -   NaBH₄ Sodium borohydride.    -   NaH Sodium hydride    -   NaHCO₃ Sodium bicarbonate    -   NaOH Sodium hydroxide    -   NH₂OH Hydroxylamine    -   NH₃ Ammonia    -   NH₄HCO₃ Ammonium bicarbonate    -   NiCl₂.6H₂O Nickel (II) chloride hexahydrate    -   NMM 4-Methylmorpholine    -   O₂ (g) Oxygen (gas)    -   Pd(dppf)Cl₂        [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)    -   PtO₂ Platinum (IV) oxide    -   RuPhos 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl    -   RuPhos Pd G2 2nd Generation RuPhos Precatalyst,        Chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

Example 1 Preparation of(R)-N-hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamideand(S)-N-hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide(I-1 and I-2)

Step-1: Methyl 1-oxo-2,3-dihydro-1H-indene-5-carboxylate

Into a 1-L round-bottom flask was placed a solution of5-bromo-2,3-dihydro-1H-inden-1-one (30 g, 142 mmol, 1 equiv) in MeOH(450 mL), Pd(dppf)Cl₂ (15.6 g, 21.32 mmol, 0.15 equiv) and Et₃N (57.5 g,568 mmol, 4 equiv). CO (g) was introduced to the flask. The reactionmixture was stirred for 24 h at 100° C. in an oil bath, then cooled toroom temperature. The solids were filtered and the filtrate wasconcentrated under vacuum. The residue was purified by normal phasechromatography on silica gel using EtOAc/petroleum ether (1:10). Thecollected fractions were concentrated under vacuum to afford 18 g (67%yield) of the title compound as a yellow solid. MS: (ES, m/z): 191[M+H]⁺.

Step-2: Dimethyl 1-oxo-2,3-dihydro-1H-indene-2,5-dicarboxylate

Into a 250-mL round-bottom flask was placed a solution of methyl1-oxo-2,3-dihydro-1H-indene-5-carboxylate (10 g, 52.58 mmol, 1 equiv) indimethyl carbonate (100 mL). NaH (60% in mineral oil, 4.2 g, 175 mmol, 2equiv) was added. The resulting solution was stirred for 2 h at 80° C.in an oil bath. The reaction mixture was cooled to room temperature andpoured into ice water (50 mL). The solids were filtered and the filtratewas extracted with EtOAc (3×100 mL). The combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. Theresidue purified by normal phase chromatography on silica gel usingEtOAc/petroleum ether (1:10). The collected fractions were concentratedunder vacuum to afford 5.8 g (44% yield) of the title compound as ayellow solid. MS: (ES, m/z): 249 [M+H]⁺.

Step-3: Dimethyl2-(cyanomethyl)-1-oxo-2,3-dihydro-1H-indene-2,5-dicarboxylate

Into a 1-L, round-bottom flask was placed a solution of dimethyl1-oxo-2,3-dihydro-1H-indene-2,5-dicarboxylate (11.8 g, 47.54 mmol, 1equiv) in THF (500 mL). Et₃N (24.0 g, 237.68 mmol, 5 equiv) and2-bromoacetonitrile (17.1 g, 142.61 mmol, 3 equiv). The reaction wasstirred for 16 h at 25° C. The solids were filtered out and the filtratewas concentrated under vacuum. The residue was purified by normal phasechromatography on silica gel using EtOAc/petroleum ether (1:5). Thecollected fractions were concentrated under vacuum to afford 3.1 g (23%yield) of the title compound as a yellow solid. MS: (ES, m/z): 288[M+H]⁺.

Step 4: Dimethyl2-(2-aminoethyl)-1-hydroxy-2,3-dihydro-1H-indene-2,5-dicarboxylate

Into a 500-mL round-bottom flask was placed dimethyl2-(cyanomethyl)-1-oxo-2,3-dihydro-1H-indene-2,5-dicarboxylate (3 g,10.44 mmol, 1 equiv), MeOH (100 mL), PtO₂ (3 g) and AcOH (30 mL). H₂ (g)was introduced into the flask. The resulting solution was stirred for 4h at 25° C. The reaction mixture was cooled to room temperature and thesolids were filtered out. The filtrate was concentrated under vacuum toafford 2 g (crude) of the title compound as a yellow oil. MS: (ES, m/z):294 [M+H]⁺.

Step-5: Methyl1-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate

Into a 250-mL round-bottom flask was placed dimethyl2-(2-aminoethyl)-1-hydroxy-2,3-dihydro-1H-indene-2,5-dicarboxylate (2 g,6.82 mmol, 1 equiv) and NH₃ (7 M in MeOH, 30 mL). The reaction wasstirred for 1 h at 25° C. The resulting mixture was concentrated undervacuum. The crude product was re-crystallized from CH₂Cl₂ to afford 500mg (28% yield) of the title compound as a white solid, MS: (ES, m/z):262 [M+H]⁺.

Step-6: Methyl2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate

Into a 100-mL round-bottom flask was placed a solution of methyl1-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate(900 mg, 3.44 mmol, 1 equiv) in TFA (10 mL) and triethylsilane (10 mL).The reaction was stirred for 12 h at 80° C. in an oil bath. The reactionmixture was cooled to room temperature and concentrated under vacuum.The residue was purified by normal phase chromatography on silica gelusing an EtOAc/petroleum ether gradient. The collected fractions wereconcentrated under vacuum to afford 400 mg of the title compound as awhite solid. MS: (ES, m/z): 246 [M+H]⁺.

Step-7: Chiral separation of methyl(R)-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate andmethyl(S)-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate

Racemic methyl2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate waspurified by Chiral-Prep-HPLC with the following conditions: Column:Phenomenex Lux® Cellulose-4 AXIA™ Packed, 250×21.2 mm, 5 μm; MobilePhase A: hexanes, Mobile Phase B: EtOH; Gradient: hold 30% B for 23 min;Detector: UV 254 nm and 220 nm. The first eluting isomer (Rt 2.46 min)was collected and concentrated under vacuum to afford 210 mg (25% yield)of a white solid which was assigned as the R isomer of methyl2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate. MS: (ES,m/z): 246 [M+H]⁺. The second eluting isomer (Rt 3.21 min) was collectedand concentrated under vacuum to afford 200 mg (24% yield) of a whitesolid which was assigned as the S isomer of methyl2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate. MS: (ES,m/z): 246 [M+H]⁺.

Step-8: Methyl(R)-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate

Into an 8-mL vial was placed a solution of the first eluted isomer fromStep 7, which was assigned as methyl(R)-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate asdescribed above, (50 mg, 0.20 mmol, 1 equiv) in DMF (3 mL). The solutionwas cooled to 0° C. NaH (60% in mineral oil, 16.3 mg, 0.41 mmol, 2equiv), was added in portions at 0° C. The resulting solution wasstirred for 30 min at 0° C. CH₃I (57.8 mg, 0.41 mmol, 2 equiv) was addedand the resulting solution was stirred for 2 h at 25° C. The reactionmixture was poured into 10 mL of water and extracted with EtOAc (2×20mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under vacuum to afford 30 mg (51% yield) of the titlecompound as a yellow solid. MS: (ES, m/z): 260 [M+H]⁺.

Step-9:(R)-N-Hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide

Into an 8-mL vial was placed methyl(R)-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate(30 mg, 0.12 mmol, 1 equiv), THF/MeOH (4:1, 2.5 mL), NH₂OH (50% inwater, 917 mg, 27.79 mmol, 120 equiv) and aq. 1N NaOH (0.232 mL, 0.24mmol). The resulting solution was stirred for 2 h at 25° C. The crudeproduct was purified by Prep-HPLC with the following conditions: Column:XBridge Prep C18 OBD, 19×150 mm, 5 μm; Mobile Phase A: Water/0.1% Formicacid, Mobile Phase B: CH₃CN; Gradient: 5% B up to 20% B in 7 min;Detector: UV 254 nm, 220 nm. The collected fractions were lyophilized toafford 11.6 mg (39% yield) of the title compound as a light pink solid.¹H NMR (300 MHz, DMSO-d6) δ (ppm): 11.13 (s, 1H), 9.04 (s, 1H),7.58-7.53 (t, J=7.4 Hz, 2H), 7.27-7.24 (d, J=7.8 Hz, 1H), 3.35-3.31 (t,J=6.6 Hz, 2H), 3.17-3.11 (d, J=16.2 Hz, 2H), 2.88-2.83 (d, J=16.2 Hz,2H), 2.79 (s, 3H), 1.98-1.94 (t, J=6.6 Hz, 2H). MS: (ES, m/z): 261[M+H]⁺.

Step-10: Methyl(S)-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate

The procedure from Step 8 was followed using the second eluted isomerfrom Step 7, which was assigned as methyl(S)-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate asdescribed above, (50 mg, 020 mmol, 1 equiv) to afford 53 mg (94% yield)of the title compound as a light yellow oil. MS: (ES, m/z): 260 [M+H]⁺.

Step-11:(S)-N-Hydroxy-1′-methyl-2′-oxo-1,3-dihydrospirol[indene-2,3′-pyrrolidine]-5-carboxamide

The procedure from Step 9 was followed using methyl(S)-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate(53 mg, 0.20 mmol, 1 equiv) to afford 20.9 mg (39% yield) of the titlecompound as a white solid. ¹H NMR (300 MHz, DMSO-d6) δ (ppm): 11.11 (m,1H), 8.98 (s. 1H), 7.59-7.54 (m, 2H), 7.28-7.25 (m, 1H), 3.36-3.32 (m,2H), 3.18-3.16 (d, J=3.3 Hz, 1H), 3.12-3.11 (d, J=3.0 Hz, 1H), 2.89 (s,1H), 2.84 (s, 1H), 2.80-2.75 (m, 3H), 1.99-1.95 (m, 2H). MS: (ES, m/z):261 [M+H]⁺.

TABLE 1 The following compounds were prepared according to the method ofExample 1, with stereochemistry assigned as described, with thefollowing modifications: (1) In Steps 8 and 10, the halide can be aniodide, a chloride, or a bromide; (2) In Steps 9 and 11, the Prep-HPLCcolumn can be XBridge Prep C18 OBD, 19 × 150 mm, 5 μm using formic acidor NH₄HCO₃ as the additive to the water Mobile Phase A; or the columnXBridge Shield RP18 OBD, 19 × 150 mm, 5 μm using formic acid as theadditive to the water Mobile Phase A. Found (ES, m/z) Ex. Structure¹H-NMR δ (ppm) [M + H]+ I-3

(400 MHz, DMSO-d6): 10.97 (s, 1H), 8.96 (s, 1H), 7.57 (s, 1H), 7.54 (d,J = 8.0 Hz, 1H), 7.23 (d, J = 16.8 Hz, 1H), 4.18-4.11 (m, 1H), 3.33-3.26(m, 2H), 3.14-3.10 ( (d, J = 16.8 Hz, 2H), 2.87- 2.83 (d, J = 16.0 Hz,2H), 1.94-19.1 (m, 2 H), 1.11-1.09 (m, 6H) 289 I-4

(400 MHz, DMSO-d6): 11.09 (br, 1H), 8.96 (br, 1H), 7.58 (s, 1H), 7.54(d, J = 7.6 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 4.19-4.11 (m, 1H),3.30-3.26 (m, 2H), 3.13 (d, J = 16.0 Hz, 2H), 2.86 (d, J = 16.4 Hz, 2H),1.95-1.92 (m, 2H), 1.15- 1.09 (m, 6H) 289 I-5

(300 MHz DMSO-d6): 8.55-8.41 (s, 2H), 7.58-7.53 (m, 2H), 7.26-7.24 (d, J= 8.0 Hz, 1H), 3.41-3.23 (m, 4H), 3.15- 3.10 (m, 2H), 2.88-2.84 (d, J =16.0 Hz, 2H), 1.96-1.93 (m, 2H), 1.07-1.03 (m, 3H) 275 I-6

(400 MHz, DMSO-d6): 8.96 (br, 1H), 7.58 (s, 1H), 7.55 (d, J = 8.0 Hz,1H), 7.25 (d, J = 8.0 Hz, 1H), 3.35-3.30 (m, 2H), 3.28-3.16 (m, 2H),3.15-3.11 (m, 2H), 2.88-2.84 (m, 2H), 2.08-1.94 (m, 2H), 1.15-1.02 (m,3H) 275 I-7

(400 MHz, DMSO-d6): 11.06 (s, 1H), 8.98 (s, 1H), 7.58 (s, 1H), 7.54 (d,J = 7.6 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 3.34-3.31 (m, 2H), 3.16-3.12(m, 2H), 3.05-3.04 (m, 2H), 2.90-2.86 (m, 2H), 1.91-1.87 (m, 3H),0.85-0.83 (m, 6H) 303 I-8

(400 MHz, DMSO-d6): 11.10 (br s, 1H), 8.98 (br s, 1H), 7.58 (s, 1H),7.55 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 3.35 (s, 1H), 3.32(s, 1H), 3.15 (d, J = 16.0 Hz, 2H), 3.06-3.04 (m, 2H), 2.89 (d, J = 12.0Hz, 2H), 1.98-1.88 (m, 3H), 0.85-0.81 (m, 6H) 303 I-9

(400 MHz, DMSO-d6): 11.02 (s, 1H), 9.02 (s, 1H), 7.59 (s, 1H), 7.55 (d,J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.21-7.12 (m, 4H), 4.44 (s,2H), 3.22- 3.16 (m, 4H), 2.93-2.89 (m, 2H), 2.25 (s, 3H), 1.97-1.95 (m,2H) 351 I-10

(400 MHz, DMSO-d6): 11.12 (br, 1H), 8.97 (br, 1H) 7.60 (s, 1H) 7.55 (d,J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.21-7.15 (m, 3H), 7.13 (d, J= 3.6 Hz, 1H), 4.44 (s, 2H), 3.22-3.16 (m, 4H), 2.92 (d, J = 16.0 Hz,1H), 2.32 (s, 3H), 1.99-1.96 (m, 2H) 351 I-12

(300 MHz, DMSO-d6): 11.12 (s, 1H), 8.98 (s, 1H), 7.61-7.58 (m, 1H),7.57- 7.55 (m, 1H), 7.41-7.37 (m, 2H), 7.33- 7.31 (m, 1H), 7.30-7.23 (m,3H), 4.45 (s, 2H), 3.27-3.23 (m, 2H), 3.19 (s, 1H), 2.95 (s, 1H), 2.90(s, 1H), 2.08- 1.97 (m, 2H) 337

Example 2 Preparation of(R)-1′-benzyl-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide(I-11)

Step-1:(R)-1′-Benzyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylicacid

Into an 8-mL vial was placed a solution of the first eluted isomer fromExample 1, Step 7, which was assigned as methyl(R)-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate asdescribed above, (50 mg, 0.20 mmol, 1 equiv) in DMF (3 mL). The reactionwas cooled to 0° C. and NaH (60% in mineral oil, 16.3 mg, 0.41 mmol) wasadded portionwise at 0° C. The resulting solution was stirred for 30 minat 0° C. (Bromomethyl)benzene (69.7 mg, 0.41 mmol) was added at 0° C.The reaction was stirred for 2 h at 25° C. The reaction was then pouredinto 10 mL water. The solution was adjusted to pH 2 with 2N HCl andextracted with EtOAc (2×10 mL). The organic layers were combined, driedover Na₂SO₄, filtered and concentrated under vacuum to afford 40 mg (49%yield) of the title compound as a yellow oil. MS: (ES, m/z): 322 [M+H]⁺.

Step-2:(R)-1′-Benzyl-1-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide

Into an 8-mL vial was placed(R)-1′-benzyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5carboxylicacid (40 mg, 0.12 mmol, 1 equiv) in DMA (3 mL). This was followed by theaddition of isopropyl chloroformate (78.7 mg, 0.64 mmol, 5 equiv) andNMM (63.1 mg, 0.62 mmol, 5 equiv) dropwise with stirring at 0° C. Theresulting solution was stirred for 30 min at 0° C. To the mixture wasadded a solution of NH₂OH.HCl (43.7 mg, 0.62 mmol, 5 equiv) in DMA (0.5mL). The reaction was stirred for 16 h at 25° C. The solids werefiltered out and the crude product was purified by Prep-HPLC with thefollowing conditions: Column: XBridge Prep C18 OBD, 19×150 min, 5 μm;Mobile Phase A: Water/0.1% Formic acid, Mobile Phase B: CH₃CN; Gradient:25% B up to 55% B in 7 min; Detector: UV 254 nm, 220 nm. The collectedfractions were lyophilized to afford 16.9 mg (40% yield) of the titlecompound as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ (ppm): 11.10(s, 1H), 8.98 (s, 1H), 7.60-7.54 (m, 2H), 7.40-7.23 (m, 6H), 4.44 (s,2H), 3.25-3.18 (m, 4H), 2.93-2.89 (d, J=12 Hz, 2H), 1.99-1.92 (m, 2H).MS: (ES, m/z): 337 [M+H]⁺.

Example 3 Preparation of(R)-N-hydroxy-2′-oxo-1-phenyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide(I-13)

Step-1: Methyl(R)-2′-oxo-1′-phenyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate

Into a 100-mL round-bottom flask was placed a solution of the firsteluted isomer from Example 1, Step 7, which was assigned as methyl(R)-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate asdescribed above, (50 mg, 0.20 mmol, 1 equiv) in CH₂Cl₂ (10 mL). Cu(OAc)₂(69.8 mg, 0.380 mmol, 2 equiv), Et₃N (58.2 mg, 0.58 mmol, 3 equiv),phenylboronic acid (117 mg, 0.96 mmol, 5 equiv) and 4 Å molecular sieves(100 mg) were added. O₂ (g) was introduced to the reaction mixture. Theresulting solution was stirred for 60 h at 25° C. The solids werefiltered out and the filtrate was diluted with 10 mL of water andextracted with CH₂Cl₂ (3×10 mL). The combined organic layers were driedover Na₂SO₄ and concentrated under vacuum to afford 20 mg (29% yield) ofthe title compound as an orange oil. MS: (ES, m/z): 322 [M+H]⁺.

Step-2:(R)-N-Hydroxy-2′-oxo-1′-phenyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide

Into an 8-mL vial was placed a solution of methyl(R)-2′-oxo-1′-phenyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate(20 mg, 0.06 mmol, 1 equiv) in THF/MeOH (4:1, 2.5 mL). Then NH₂OH (50%in water, 492 mg, 7.45 mmol, 120 equiv) was added followed by aq. 1NNaOH (0.124 mL, 2 equiv). The resulting solution was stirred for 2 h at25° C. The crude product was purified by Prep-HPLC with the followingconditions: Column: XBridge Prep C18 OBD, 19×150 mm, 5 μm; Mobile PhaseA: Water/0.1% Formic acid, Mobile Phase B: CH₃CN, Gradient: 5% B up to57% B in 7 min; Detector: UV 254 nm, 220 nm. The collected fractionswere lyophilized to afford 6.7 mg (33% yield) of the title compound as awhite solid. ¹H NMR (300 MHz, DMSO-d6) δ (ppm): 10.88 (s, 1H), 9.00 (s,1H), 7.73-7.71 (d, J=7.8 Hz, 2H), 7.61-7.56 (t, J=8.4 Hz, 6H), 7.42-7.37(t, J=8.0 Hz, 2H), 7.30-7.27 (d, J=7.8 Hz, 1H), 7.18-7.13 (t, J=7.4 Hz,1H) 3.89-3.84 (t, J=6.8 Hz, 2H), 3.24 (s, 2H), 3.05-2.99 (d, J=16.2 Hz,2H), 2.15-2.07 (m, 2H). MS: (ES, m/z): 323 [M+H]⁺.

Example 4 Preparation of(S)-N-hydroxy-2′-oxo-1′-phenyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide(I-14)

Step-1: Methyl(S)-2′-oxo-1′-phoryl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate

Into a 25-mL round-bottom flask was placed a solution of the secondeluted isomer from Example 1, Step 7, which was assigned as methyl(S)-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate asdescribed above, (50 mg, 0.20 mmol, 1 equiv) in THF (8.0 mL). Cu(OAc)₂(37 mg, 0.20 mmol, 1 equiv), Et₃N (62 mg, 0.61 mmol, 3 equiv), pyridine(24 mg, 0.31 mmol, 1.5 equiv), phenylboronic acid (^(49.7) mg, 0.41mmol, 2 equiv) and 4 Å molecular sieves were added. O₂ (g) wasintroduced in. The resulting solution was stirred for 18 h at 60° C. inan oil bath. The solids were filtered out and the filtrate wasconcentrated under vacuum. The residue was dissolved in 60 mL of EtOAcand was washed with 3×20 mL of H₂O. The organic layer was separated andconcentrated under vacuum. The residue purified by normal phasechromatography on silica gel using EtOAc/petroleum ether (1:2). Thecollected fractions were concentrated under vacuum to afford 60 mg (92%)of the title compound as a light yellow oil. MS: (ES, m/z): 322 [M+H]⁺.

Step-2:(S)-N-Hydroxy-2′-oxo-1′-phenyl-1,3-dihydrospiro[indene-2,3′-pyrrolidin]-5-carboxamide

Into an 8-mL vial was placed a solution of methyl(S)-2′-oxo-1′-phenyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate(60 mg, 0.19 mmol, 1 equiv) in THF/MeOH (4:1, 2.5 mL). Then NH₂OH (50%in water, 274 mg, 5.37 mmol, 30 equiv) was added followed by aq 1N NaOH(0.37 mL, 2 equiv). The resulting solution was stirred for 1 h at 25° C.The crude product was purified by Prep-HPLC with the followingconditions: Column: XBridge Prep C18 OBD, 19×150 mm, 5 μm; Mobile PhaseA: Water/0.1% Formic acid, Mobile Phase B: CH₃CN; Gradient: 5% B up to57% B in 7 min; Detector: UV 254 nm, 220 nm. The collected fractionswere lyophilized to afford 24.3 mg (40% yield) of the title compound asan off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ (ppm): 11.14 (s, 1H),9.00 (s, 1H), 7.75-7.72 (m, 2H), 7.63-7.57 (m, 2H), 7.44-7.38 (m, 2H),7.32-7.29 (m, 1H), 7.19-7.14 (m, 1H), 3.90-3.86 (m, 2H), 3.34-3.25 (m,2H), 3.06-3.01 (d, J=16.2 Hz, 2H), 2.16-2.08 (m, 2H). MS: (ES, m/z): 323[M+H]⁺.

TABLE 2 The following compounds were prepared according to the method ofExample 4, with stereochemistry assigned as described, with thefollowing modification: In the Prep-HPLC purification of Step 2, formicacid or NH₄HCO₃ can be used as the additive to the water Mobile Phase A.Found (ES, m/z) Ex. Structure ¹H-NMR δ (ppm) [M + H]+ I-15

(400 MHz, DMSO-d6): 10.71 (s, 1H), 8.95 (s, 1H), 7.74-7.71 (m, 2H),7.60- 7.54 (m, 2H), 7.28-7.20 (m, 3H), 3.85- 3.82 (m, 2H), 3.30-63.22(m, 2H), 3.02- 2.98 (m, 2H), 2.12-2.09 (m, 2H) 341 In Step 1, using1^(st) eluted isomer assigned as R I-16

(400 MHz, DMSO-d6): 11.10 (br s, 1H), 8.98 (br s, 1H), 7.77-7.73 (m,2H), 7.62 (s, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H),7.27-7.22 (m, 2H), 3.88-3.84 (m, 2H), 3.29-3.23 (m, 2H), 3.04-3.00 (m,2H), 2.14-2.11 (m, 2H) 341 In Step 1, using 2^(nd) eluted isomerassigned as S I-18

(400 MHz, DMSO-d6): 8.95-8.94 (m, 2H), 8.37-8.36 (m, 1H), 8.17-8.15 (m,1H), 7.62 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.46-7.42 (m, 1H), 7.30 (d,J = 8.0 Hz, 1H), 3.93-3.90 (m, 2H), 3.32-3.29 (m, 1H), 3.26-3.25 (m, 1H)3.07-3.02 (m, 2H), 2.19-2.07 (m, 2H) 324 In Step 1, using 2^(nd) elutedisomer tentatively assigned as S

Example 5 Preparation of(R)-N-hydroxy-2′-oxo-1′-(pyridin-3-yl)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide(I-17)

Step-1: Methyl(R)-2′-oxo-1′-(pyridin-3-yl)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate

Into a 10-mL sealed tube was placed a solution of the first elutedisomer from Example 1, Step 7, which was assigned as methyl(R)-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate asdescribed above, (60 mg, 0.24 mmol, 1 equiv) in toluene (5 mL),3-bromopyridine (77 mg, 0.49 mmol, 2 equiv), RuPhos (23 mg, 0.05 mmol),Cs₂CO₃ (240 mg, 0.74 mmol, 3 equiv) and RuPhos Pd G2 (19 mg, 0.02 mmol,0.1 equiv). The reaction was stirred for 16 h at 110° C. The reactionmixture was then cooled to room temperature and poured into 15 mL ofwater. The resulting solution was extracted with 3×30 mL of EtOAc. Thecombined organic layers were washed with 100 mL of brine, dried overNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby normal phase chromatography on silica gel using EtOAc/petroleum ether(1:1). The collected fractions were concentrated under vacuum to afford51 mg (60% yield) of the title compound as a yellow oil. MS: (ES, m/z):323 [M+H]⁺.

Step-2:(R)-N-Hydroxy-2′-oxo-1′-(pyridin-3-yl)-1.3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide

Into a 25-mL round-bottom flask was placed methyl(R)-2′-oxo-1′-(pyridin-3-yl)-1,3-dihydrospiro[indene-2,3′-pyrolidine]-5-carboxylate(51 mg, 0.16 mmol, 1 equiv), THF/MeOH (4:1, 4 mL), NH₂OH (50% in water,1426 mg, 43.17 mmol, 120 equiv) and aq. 1N NaOH (0.32 mL, 0.32 mmol, 2equiv). The resulting solution was stirred for 2 h at room temperature.The solids were filtered out and the crude product was purified byPrep-HPLC with the following conditions: Column: XBridge Prep C18 OBD,19×150 mm, 5 μm; Mobile Phase A: Water/0.1% Formic acid, Mobile Phase B:CH₃CN, Gradient: 5% B up to 14% B in 8 min; Detector: UV 254 nm, 220 nm.The collected fractions were lyophilized to afford 20.1 mg (39% yield)of the title compound as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ(ppm): 8.94 (s, 1H), 8.37 (d, J=3.9 Hz, 1H), 8.17 (d, J=20.4 Hz, 1H),7.61-7.56 (m, 2H), 7.50-7.46 (m, 1H), 7.34 (d, 7.8 Hz, 1H), 3.93 (d,J=6.6 Hz, 2H), 3.29 (d, J=16.5 Hz, 2H), 3.07 (d, J=16.2 Hz, 2H),2.20-2.16 (m, 2H). MS: (ES, m/z): 324 [M+H]⁺.

TABLE 3 The following compounds were prepared according to the method ofExample 5, with stereochemistry assigned as described, with thefollowing modification: In the Prep-HPLC purification of Step 2, formicacid or NH₄HCO₃ can be used as the additive to the water Mobile Phase A.Found (ES, m/z) Ex. Structure ¹H-NMR δ (ppm) [M + H]+ I-19

(300 MHz, DMSO-d6): 11.11 (s, 1H), 8.98 (s, 1H), 8.43-8.41 (m, 1H), 8.33(d, J = 8.4 Hz, 1H), 7.86- 7.81 (m, 1H), 7.62-7.57 (m, 2H), 7.30 (d, J =7.8 Hz, 1H), 7.19-7.15 (m, 1H), 4.05-4.00 (m, 2H), 3.30 (d, J = 17.7 Hz,2H), 3.08 (d, J = 16.5 Hz., 2H), 2.14-2.08 (m, 2H) 324 In Step 1, using1^(st) eluted isomer assigned as R I-20

(400 MHz, DMSO-d6): 8.43-8.41 (m, 1H), 8.34-8.32 (m, 1H), 7.86- 7.81 (m,1H), 7.29 (d, J = 8.0 Hz, 1H), 7.19-7.15 (m, 1H), 4.04-4.01 (m, 2H),3.32-3.27 (m, 2H), 3.07- 3.03 (m, 2H), 2.14-2.07 (m, 2H) 324 In Step 1,using 2^(nd) eluted isomer assigned as S I-21

(300 MHz, DMSO-d6): 11.11 (s, 1H), 9.00 (d, J = 11.4 Hz, 1H), 8.52 (d, J= 6.3 Hz, 2H), 7.75-7.73 (m, 2H), 7.62-7.57 (m, 2H), 7.30 (d, J = 7.8Hz, 1H), 3.91-3.86 (m, 2H), 3.32-3.30 (m, 1H), 3.25 (s, 1H), 3.08 (s,1H), 3.02 (s, 1H), 2.18- 2.07 (m, 2H) 324 In Step 1, using 1^(st) elutedisomer assigned as R I-22

(400 MHz, DMSO-d6): 11.12 (br s, 1H), 8.96 (br s, 1H), 8.53- 8.51 (m,2H), 7.75-7.73 (m, 2H), 7.62 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.29 (d,J = 8.0 Hz, 1H), 3.90-3.87 (m, 2H), 3.29-3.25 (m, 2H), 3.07-3.03 (m,2H), 2.18-2.07 (m, 2H) 324 In Step 1, using 2^(nd) eluted isomerassigned as S

Example 6 Preparation of(R)-N-hydroxy-2′-oxo-1′-(pyridin-3-ylmethyl)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide(I-23)

Step-1: Methyl(R)-2′-oxo-1′-(pyridin-3-ylmethyl)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate

Into a 25-mL round-bottom flask was placed a solution of the firsteluted isomer from Example 1, Step 7, which was assigned as methyl(R)-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate asdescribed above, (50 mg, 0.20 mmol, 1 equiv) in DMF (3 mL). NaH (60% inmineral oil, 16 mg, 0.40 mmol, 2 equiv) was then added at 0° C. Theresulting solution was stirred for 30 min at 0° C. A solution of3-(bromomethyl) pyridine hydrobromide (77 mg, 0.30 mmol, 1.5 equiv) andEt₃N (61 mg, 0.60 mmol, 3 equiv) in DMF (1 mL) were added dropwise withstirring at 0° C. The resulting solution was allowed to stir for 1 h atroom temperature. The reaction mixture was then poured into 15 mL of icewater and extracted with 3×15 mL of EtOAc. The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under vacuum to afford55 mg of the title compound as a yellow oil. MS: (ES, m/z): 337 [M+H]⁺.

Step-2:(R)-N-Hydroxy-2′-oxo-1′-(pyridin-3-ylmethyl)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide

Into a 25-mL round-bottom flask was placed methyl(R)-2′-oxo-1′-(pyridin-3-ylmethyl)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate(55 mg, 0.16 mmol, 1 equiv), THF/MeOH (4:1, 3.0 mL), NH₂OH (50% inwater, 648 mg, 9.81 mmol, 60 equiv) and aq. 1N NaOH (0.32 mL, 0.32 mmol,2 equiv). The resulting solution was stirred for 2 h at 25° C. Thesolids were filtered and the crude product was purified by Prep-HPLCwith the following conditions: Column: XBridge Prep C18 OBD, 19×150 mm,5 μm; Mobile Phase A: Water/0.1% Formic acid, Mobile Phase B: CH₃CN;Gradient: 3% B up to 23% B in 7 min; Detector: UV 254 nm, 220 nm. Thecollected fractions were lyophilized to afford 19.6 mg (36% yield) ofthe title compound as a light pink solid. ¹H NMR (400 MHz, DMSO-d6) δ(ppm): 11.05 (s, 1H), 8.95 (s, 1H), 8.51-8.47 (m, 2H), 7.64-7.52 (m,3H), 7.40-7.39 (m, 1H), 7.37-7.24 (m, 1H), 4.46 (s, 2H), 3.27-3.24 (m,2H), 3.19-3.15 (d, J=16.4 Hz, 2H), 2.92-2.88 (d, J=16.4 Hz, 2H),1.99-1.95 (m, 2H) MS: (ES, m/z): 338 [M+H]⁺.

Example 7 Preparation of(R)-N-hydroxy-1′-methyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamideand(S)-N-hydroxy-1′-methyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide(I-24 and I-25)

Step 1: Methyl2′-thioxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate

Into a 100-mL round-bottom flask was placed methyl2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate (2.4 g,9.78 mmol, 1 equiv), CH₂Cl₂ (30 mL) and2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane(Lawesson reagent) (5.9 g, 14.59 mmol, 1.5 equiv). The resultingsolution was stirred for 16 h at room temperature. The reaction was thenquenched by the addition of aq NaHCO₃ (30 mL). The resulting solutionwas extracted with 3×30 mL of CH₂Cl₂. The organic layers were combined,dried over Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by normal phase column chromatography on silica gel usingEtOAc/petroleum ether (1:1). The collected fractions were concentratedunder vacuum to afford 2 g (78% yield) of the title compound as a yellowsolid. MS: (ES, m/z): 262 [M+H]⁺.

Step-2: Methyl 1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed methyl2′-thioxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate (2 g,7.65 mmol, 1 equiv), THF (40 mL), MeOH (10 mL) and NiCl₂.6H₂O (10.9 g,45.86 mmol, 6 equiv). This was followed by the addition of NaBH₄ (1.74g, 45.99 mmol, 6 equiv in several batches at 0° C. The resultingsolution was stirred for 18 h at room temperature. The reaction wasconcentrated under vacuum. The residue was dissolved in 10 mL of THF andfiltered through a Celite pad. The filtrate was concentrated underreduced pressure and the residue was purified by normal phase columnchromatography on silica gel using CH₂Cl₂/MeOH (10:1). The collectedfractions were concentrated under vacuum to afford 1.4 g (79% yield) ofthe title compound as a green solid. MS: (ES, m/z): 232 [M+H]⁺.

Step-3: 1′-(tert-Butyl) 5-methyl(R)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-1′,5-dicarboxylate and1′-(tert-Butyl) 5-methyl(S)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-1′,5-dicarboxylate

Into a 50-mL round-bottom flask was placed methyl1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate (1.4 g, 6,05mmol, 1 equiv), CH₂Cl₂ (15 mL), Et₃N (2.4 g, 23.72 mmol, 4 equiv) anddi-tert-butyl dicarbonate (3.3 g, 15.12 mmol, 2.5 equiv). The resultingsolution was stirred for 18 h at room temperature. The reaction was thenquenched by the addition of 20 mL of water. The resulting solution wasextracted with 3×20 mL of CH₂Cl₂. The combined organic layers were driedover Na₂SO₄, filtered, concentrated under vacuum, and the residue waspurified by normal phase column chromatography on silica gel usingEtOAc/petroleum ether (1:10) to afford the racemic mixture of the titlecompounds. The racemate was further separated by Prep-SFC with thefollowing conditions: Column: EnantioCel-C1, 21.2×250 mm; Mobile PhaseA: CO₂, Mobile Phase B: EtOH; Gradient 20% B; Flow rate: 40 mL/min;Detector: UV 220 nm. The first eluting isomer (Rt 4.91 min) wascollected and concentrated under vacuum to give 400 mg (20% yield) of awhite solid which was assigned as the R isomer of 1′-(tert-butyl)5-methyl 1,3-dihydrospiro[indene-2,3′-pyrrolidine]-1′,5-dicarboxylate.MS: (ES, m/z): 332 [M+H]⁺. The second eluting isomer (Rt 5.76 min) wascollected and concentrated under vacuum to give 400 mg (20% yield) of awhite solid which was assigned as the S isomer of 1′-(tert-butyl)5-methyl 1,3-dihydrospiro[indene-2,3′-pyrrolidine]-1′,5-dicarboxylate.MS: (ES, m/z): 332 [M+H]—F.

Step 4: Methyl(R)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate

Into a 25-mL round-bottom flask was placed the first eluted isomer fromStep 3, which was assigned as 1′-(tert-butyl) 5-methyl(R)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-1′,5-dicarboxylate asdescribed above, (400 mg, 1.21 mmol, 1 equiv), CH₂Cl₂ (8 mL) and TFA (2mL). The reaction was stirred for 2 h at room temperature. The reactionwas concentrated under vacuum. The residue was dissolved in water (10mL) and the pH was adjusted to 8 with aq. NaHCO₃. The resulting solutionwas extracted with 3×15 mL of CH₂Cl₂. The combined organic layers weredried over Na₂SO₄, filtered and concentrated under vacuum to afford 270mg (97% yield) of the title compound as a yellow oil. MS: (ES, m/z): 232[M+H]⁺.

Step-5: Methyl(R)-1′-methyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate

Into a 10-mL round-bottom flask was placed methyl(R)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate (50 mg, 0.22mmol, 1 equiv), MeOH (3 mL) and paraformaldehyde (7.8 mg, 0.26 mmol, 1.2equiv). The resulting solution was stirred for 1 h at room temperature.This was followed by the addition of NaBH₃CN (42 mg, 0.67 mmol, 3 equiv)in several batches at 0° C. The reaction was allowed to stir for 18 h atroom temperature. The reaction was poured into 15 mL of water. Theresulting solution was extracted with 3×15 mL of EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated undervacuum. The residue was purified by normal phase column chromatographyon silica gel using EtOAc/petroleum ether (1:2). The collected fractionswere concentrated under vacuum to afford 50 mg (94% yield) of the titlecompound as a yellow oil. MS: (ES, m/z): 246 [M+H]⁺.

Step-6:(R)-N-Hydroxy-1′-methyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide

Into a 10-mL round-bottom flask was placed methyl(R)-1′-methyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate(50 mg, 0.20 mmol, 1 equiv), THF/MeOH (4:1, 5.0 mL), NH₂OH (50% inwater, 1.58 g, 24 mmol, 120 equiv) and aq. 1N NaOH (16.3 mg, 0.41 mmol,2 equiv). The resulting solution was stirred for 2 h at roomtemperature. The solids were filtered and the crude product was purifiedby Prep-HPLC with the following conditions: Column: XBridge Shield RP18OBD, 19×150 mm, 5 μm; Mobile Phase A: Water/NH₄HCO₃, Mobile Phase B:CH₃CN; Gradient: 0% B up to 18% B in 7 min; Detector: UV 220 nm, 254 nm.The collected fractions were lyophilized to afford 7.9 mg (16% yield) ofthe title compound as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ (ppm):7.55 (s, 1H), 7.50 (d, J=8 Hz, 1H), 7.21 (d, J=7.6 Hz, 1H), 2.97-2.84(m, 2H), 2.55-2.51 (m, 2H), 2.40 (s, 2H), 2.23 (s, 3H), 1.81-1.77 (m,2H). MS: (ES, m/z): 247 [M+H]⁺.

Step 7: Methyl(S)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate

The procedure from Step 4 was followed using the second eluted isomerfrom Step 3, which was assigned as 1′-(tert-butyl) 5-methyl(S)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-1′,5-dicarboxylate asdescribed above, (470 μm, 1.42 mmol, 1 equiv) to afford 230 μm (70%yield) of the title compound as a yellow oil. MS: (ES, m/z): 232 [M+H]⁺.

Step-8: Methyl(S)-1′-methyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate

The procedure from Step 5 was followed using methyl(S)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate (50 mg, 0.22mmol, 1 equiv) to afford 27 mg (51% yield) of the title compound as ayellow oil. MS: (ES, m/z): 246 [M+H]⁺.

Step-9:(S)-N-Hydroxy-1′-methyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide

The procedure from Step 6 was followed using methyl(S)-1′-methyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate(27 mg, 0.11 mmol, 1 equiv) to afford 9.2 mg (34% yield) of the titlecompound as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ (ppm): 7.55 (s,1H), 7.51 (d, J=7.6 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 2.95 (d, J=16.0 Hz,2H), 2.86 (d, J=16.0 Hz, 2H), 2.56-2.51 (m, 2H), 2.42-2.39 (m, 2H),2.23-2.21 (m, 3H), 1.80-1.77 (m, 2H). MS: (ES, m/z): 247 [M+H]⁺.

TABLE 4 The following compounds were prepared according to the method ofExample 7, with stereochemistry assigned as described, with thefollowing modification: in the Prep-HPLC purification of Steps 6 and 9,formic acid or NH₄HCO₃ can be used as the additive to the water MobilePhase A. Found (ES, m/z) Ex. Structure ¹H-NMR δ (ppm) [M + H]+ I-26

(400 MHz, DMSO-d6): 11.08 (s, 1H), 8.19 (s, 1H), 7.55-7.49 (m, 2H), 7.32(d, J = 4.2 Hz, 4H), 7.29-7.22 (m, 2H), 3.63 (s, 2H), 2.99-2.86 (m, 4H),2.69- 2.65 (m, 2H), 2.51 (s, 2H), 1.86-1.81 (m, 2H) 323 In Step 4, using1^(st) eluted isomer assigned as R I-27

(400 MHz, DMSO-d6): 11.07 (s, 1H), 8.18 (s, 1H), 7.54-7.48 (m, 2H),7.32- 7.28 (m, 4H), 7.25-7.15 (m, 2H), 3.64- 3.60 (m, 2H), 2.95 (d, J =16.0 Hz, 2H), 2.88 (d, J = 16.0 Hz, 2H), 2.69-2.63 (m, 2H), 2.49-2.46(m, 2H), 1.84-1.80 (m, 2H) 323 In Step 7, using 2^(nd) eluted isomerassigned as S

Example 8 Preparation of(S)-1′-acetyl-N-hydroxy-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide(I-29)

Step-1: Methyl(S)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate

Into a 50-mL round-bottom flask was placed the second eluted isomer fromExample 7 Step 3, which was assigned as 1′-(tert-butyl) 5-methyl(S)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]1′,5-dicarboxylate asdescribed above, (470 mg, 1.42 mmol, 1 equiv), TFA (5 mL) and CH₂Cl₂ (15mL). The resulting solution was stirred for 2 h at room temperature. Theresulting mixture was washed with 3×30mL of aq NaHCO₃, dried overNa₂SO₄, filtered and concentrated under vacuum to afford 230 mg (70%yield) of the title compound as a yellow oil. MS: (ES, m/z): 232 [M+H]⁺.

Step-2: Methyl(S)-1′-acetyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate

Into a 10-mL vial was placed methyl(S)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate (50 mg, 0.22mmol, 1 equiv) and CH₂Cl₂ (5 mL). This was followed by the addition ofEt₃N (109 mg, 1.08 mmol, 5 equiv) dropwise at 0° C. Acetyl chloride (51mg, 0.65 mmol, 3 equiv) was added dropwise at 0° C. The resultingsolution was stirred for 2 h at room temperature. The reaction mixturewas poured into 20 mL of ice water and extracted with 3×30 mL of EtOAc.The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under vacuum to afford 52 mg of the title compound as ayellow oil. MS: (ES, m/z): 274 [M+H]⁺.

Step-3:(S)-1′-Acetyl-N-hydroxy-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide

Into a 25-mL round-bottom flask was placed methyl(S)-1′-acetyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxylate(62 mg, 0.23 mmol, 1 equiv), THF/MeOH (4:1, 2.0 mL), NH₂OH (50% inwater, 896 mg, 13.56 mmol, 60 equiv) and aq. 1N NaOH (0.45 mL, 0.45mmol, 2 equiv). The resulting solution was stirred for 2 h at roomtemperature. The solids were filtered and the crude product was purifiedby Prep-HPLC with the following conditions: Column: XBridge Prep C18OBD, 19×150 mm, 5 μm; Mobile Phase A: Water/0.1% Formic acid, MobilePhase B: CH₃CN; Gradient: 5% B up to 30% B in 7 min; Detector: UV 254nm, 220 nm. The collected fractions were lyophilized to afford 13.6 mg(22% yield) of the title compound as a yellow solid. ¹H NMR (300 MHz,DMSO-d6) δ (ppm): 11.07 (s, 1H), 9.09 (s, 1H), 7.59-7.54 (m, 2H),7.27-7.24 (m, 1H), 3.56-3.52 (m, 1H), 3.41-3.26 (m, 3H), 2.98-2.86 (m,4H), 1.94-1.79 (m, 5H). MS: (ES, in 275 [M+H]⁺.

TABLE 5 The following compounds were prepared according to the method ofExample 8, with stereochemistry assigned as described, with thefollowing modictication: In Step 3, the Prep- HPLC column can be XBridgePrep C18 OBD, 19 × 150 mm, 5 μm using formic acid or NH₄HCO₃ as theadditive to the water Mobile Phase A; or the column XBridge Shield RP18OBD, 19 × 150 mm, 5 μm using formic acid as the additive to the waterMobile Phase A. Found (ES, m/z) Ex. Structure ¹H-NMR δ (ppm) [M + H]+I-28

(400 MHz, DMSO-d6): 11.11 (br s, 1H), 8.99 (s, 1H), 7.60-7.54 (m, 2H),7.29-7.24 (m, 1H), 3.59-3.54 (m, 1H), 3.40 (d, J = 6.9 Hz, 2H), 3.28 (s,1H), 2.92(d, J = 7.5 HZ, 4H), 1.96-1.82 (m, 5H) 275 In Step 1, using1^(st) eluted isomer assigned as R I-30

(400 MHz, DMSO-d6): 11.09 (br s, 1H), 8.97 (s, 1H), 7.56-7.40 (m, 7H)7.30-7.20 (m, 1H), 3.62-3.49 (m, 3H), 3.36 (s, 1H), 3.01-2.91 (m, 2H),2.87 (d, J = 7.6 Hz, 2H), 1.97-1.86 (m, 2H) 337 In Step 1, using 1^(st)eluted isomer assigned as R I-31

(300 MHz, DMSO-d6): 11.09 (s, 1H), 8.97 (s, 1H), 7.60-7.39 (m, 7H),7,29- 7.19 (m, 1H), 3.74-3.71 (m, 1H), 3.63- 3.59 (m, 2H), 3.48-3.32 (m,1H), 3.15- 2.80 (m, 4H), 1.97-1.84 (m, 2H) 337 In Step 1, using 2^(nd)eluted isomer assigned as S

Example 9 Preparation of(R)-N-hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamideand(S)-N-hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide(I-32 and I-33)

Step-1: Dimethyl2-(2-cyanoethyl)-1-oxo-2,3-dihydro-1H-indene-2,5-dicarboxylate

Into a 250-mL round-bottom flask was placed dimethyl1-oxo-2,3-dihydro-1H-indene-2,5-dicarboxylate (4.4 g, 17.73 mmol, 1equiv), DMF (50 mL), Et₃N (5.3 g, 53.18 mmol, 3 equiv) andprop-2-enenitrile (2.3 g, 44.31 mmol, 2.5 equiv). The resulting solutionwas stirred for 16 h at 25° C. The reaction was diluted with 100 mL ofwater and extracted with 3×100 mL of EtOAc. The organic layers werecombined, washed with brine (2×50mL), dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by normal phasechromatography on silica gel using EtOAc/petroleurn ether (1:3). Thecollected fractions were concentrated under vacuum to afford 2.0 g (37%yield) of title compound as a yellow solid. MS: (ES, m/z): 302 [M+H]⁺.

Step-2: Dimethyl2-(3-aminopropyl)-1-hydroxy-2,3-dihydro-1H-indene-2,5-dicarboxylate

Into a 250 mL round-bottom flask was placed dimethyl2-(2-cyanoethyl)-1-oxo-2,3-dihydro-1H-indene-2,5-dicarboxylate (1 g,3.32 mmol, 1 equiv), MeOH (80 mL), PtO₂ (1 g, 4.40 mmol, 1.33 equiv) andAcOH (20 mL). H₂ was introduced to the flask and the reaction wasstirred for 1 h at 25° C. The solids were filtered out and the filtratewas concentrated under vacuum to afford 900 mg of title compound as abrown oil. MS: (ES, m/z): 308 [M+H]⁺.

Step-3: Methyl1-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxylate

Into a 250-mL round-bottom flask was placed dimethyl2-(3-aminopropyl)-1-hydroxy-2,3-dihydro-1H-indene-2,5-dicarboxylate (1g, 3.25 mmol, 1 equiv). A solution of 7M NH₃ in MeOH (30 mL) was addeddropwise with stirring at 0° C. The resulting solution was stirred for 1h at 25° C. The reaction was concentrated under vacuum. The residuepurified by normal phase chromatography on silica gel using CH₂Cl₂/MeOH(20:1). The collected fractions were concentrated under vacuum to afford1 g of the title compound as a brown oil. MS: (ES, m/z): 276 [M+H]⁺.

Step-4: Methyl(R)-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxylate andMethyl (S)-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxylate

Into a 100-mL round-bottom flask was placed methyl1-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxylate(1 g, 3.63 mmol, 1 equiv), TFA (25 mL) and triethylsilane (25 mL). Theresulting solution was stirred overnight at 80° C. in an oil bath. Aftercooling to room temperature, the reaction was concentrated under vacuum.The residue purified by normal phase chromatography on silica gel usingEtOAc/petroleum ether (99:1). The product was purified byChiral-Prep-HPLC with the following conditions: Column: Phenomenex Lux®Cellulose-4 AXIA™ Packed, 250×21.2 mm, 5 μm; Mobile Phase A: hexanes,Mobile Phase B: EtOH; Gradient: 30% B in 23 min; Detector: UV 254 nm,220 nm. The first eluting isomer (Rt 2.8 min) was collected andconcentrated under vacuum to give 310 mg (33% yield) of an off-whitesolid which was assigned as the R isomer of methyl2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxylate. MS: (ES,m/z): 260 [M+H]⁺. The second eluting isomer (Rt 3.8 min) was collectedand concentrated under vacuum to give 280 mg (30% yield) of an off-whitesolid which was assigned as the R isomer of methyl2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxylate. MS: (ES,m/z): 260 [M+H]⁺.

Step 5: Methyl(R)-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxylate

Into a 10-mL vial purged and maintained with an inert atmosphere ofnitrogen, was placed a solution of the first eluted isomer from Step 4,which was assigned as methyl(R)-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxylate asdescribed above, (50 mg, 0.19 mmol, 1 equiv) in DMF (2 mL). The solutionwas cooled to 0° C. and NaH (60% in mineral oil, 31 mg, 0.78 mmol, 4equiv) was added. The mixture was allowed warm to room temperature andstirred for 30 min. CH₃I (109 mg, 0.77 mmol, 4 equiv) was added and thereaction was stirred for 2 h at 25° C. The reaction was then quenched bythe addition of 20 mL of water and extracted with 3×20 mL of EtOAc. Theorganic layers were combined, washed with 2×50 mL of brine, dried overNa₂SO₄, filtered and concentrated under vacuum to afford 70 mg (crude)of title compound as a brown oil. MS: (ES, m/z): 274 [M+H]⁺.

Step-6:(R)-N-Hydroxy-1′-methyl-2′-oxo-1,3dihydrospiro[indene-2,3′-piperidine]-5-carboxamide

Into a 25-mL round-bottom flask was placed methyl(R)-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxylate(70 mg, 0.26 mmol, 1 equiv), THF/MeOH (4:1, 2.0 mL), NH₂OH (50% inwater, 2023 mg, 120 equiv) and aq. 1N NaOH (0.51 mg, 2 equiv). Theresulting solution was stirred for 2 h at 25° C. The solids werefiltered out and the crude product was purified by Prep-HPLC with thefollowing conditions: Column: XBridge Prep C18 OBD, 19×150 mm 5 μm;Mobile Phase A: Water/0.05% Formic acid, Mobile Phase B: CH₃CN;Gradient: 5% B up to 14% B in 7 min; Detector: UV 254 nm, 220 nm. Thecollected fractions were lyophilized to afford 6.5 mg (9% yield) of thetitle compound as an off-white solid. ¹NMR (400 MHz, DMSO-d6) δ (ppm):10.76 (s, 1H), 8.98 (s, 1H), 7.55-7.52 (t, J=6.2 Hz, 2H), 7.23-7.21 (d,J=8.0 Hz, 1H), 3.39-3.31 (m, 4H), 2.86-2.81 (m, 5H), 1.82-1.72 (m, 4H).MS: (ES, m/z): 275 [M+H]⁺.

Step-7: Methyl(S)-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxylate

-   The procedure from Step 5 was followed using the second eluted    isomer from Step 4, which was assigned as methyl    (S)-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxylate as    described above, (50 mg, 0.19 mmol, 1 equiv) to afford 40 mg (crude)    of the title compound as a yellow solid. MS: (ES, m/z): 274 [M+H]⁺.

Step-8:(S)-N-Hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide

The procedure from Step 6 was followed using methyl(S)-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxylate(75 mg, 0.27 mmol, 1 equiv) to afford 13.4 mg (18% yield) of the titlecompound as a pink solid. ¹H NMR (400 MHz, DMSO-d6) δ (ppm): 11.08 (s,1H), 8.96 (s, 1H), 7.55 (s, 1H), 7.54-7.52 (d, J=7.6 Hz, 1H), 7.23-7.21(d, J=7.6 Hz, 1H), 3.40 (s, 1H), 3.38-3.35 (d, J=9.2 Hz, 2H), 3.31 (s,1H), 2.86-2.81 (m, 5H), 1.82-1.72 (m, 4H). MS: (ES, m/z): 275 [M+H]⁺.

Example 10 Preparation of(R)-1′-benzyl-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide(I-34)

Step-1:(R)-1′-Benzyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxylicacid

Into a 10-mL 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of the first elutedisomer from Example 9 Step 4, which was assigned as methyl(R)-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxylate asdescribed above, (50 mg, 0.19 mmol, 1 equiv) in DMF (2 mL). This wasfollowed by the portionwise addition of NaH (60% in mineral oil, 31 mg,0.78 mmol, 4 equiv) at 0° C. The mixture was stirred for 30 min at 25°C. (Bromomethyl)benzene (36 mg, 0.21 mmol, 1.09 equiv) was added. Theresulting solution was stirred for 2 h at 25° C. The reaction was thenquenched by the addition of 10 mL of water and the reaction wasextracted with 20 mL of EtOAc. The aqueous layer was adjusted to pH 4with 6N HCl and was extracted with 3×50 mL of CH₂Cl₂. The combinedorganic layers were washed with 2×50 mL of brine, dried over Na₂SO₄,filtered and concentrated under vacuum to afford 75 mg (crude) of titlecompound as a yellow oil. MS: (ES, m/z): 336 [M+H]⁺.

Step-2:(R)-1′-Benzyl-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide

Into a 25-mL round-bottom flask was placed(R)-1′-benzyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxylicacid (75 mg, 0.22 mmol, 1 equiv) and DMA (2 mL). This was followed bythe addition of isopropyl chloroformate (141 mg, 1.15 mmol, 5.14 equiv)dropwise with stiffing at 0° C. NMM (113 mg, 1.12 mmol, 5 equiv) wasadded dropwise with stirring at 0° C. The mixture was stirred for 30 minat 0° C. A solution of NH₂OH.HCl (78 mg, 1.12 mmol, 5 equiv) in DMA (1mL) was added dropwise with stirring at 0° C. The resulting solution wasstirred overnight at 25° C. The solids were filtered out and the crudeproduct was purified by Prep-HPLC with the following conditions: Column:XBridge Prep C18 OBD, 19×150 mm, 5 μm; Mobile Phase A: Water/0.1% Formicacid, Mobile Phase B: CH₃CN; Gradient: 15% B up to 55% B in 7 min;Detector: UV 254 nm, 220 nm. The collected fractions were lyophilized toafford 25.2 mg (32% yield) of title compound as an off-white solid. ¹HNMR (400 MHz, DMSO-d6) δ (ppm): 11.08 (s, 1H), 8.95 (s, 1H), 7.57-7.53(m, 2H), 7.38-7.34 (m, 2H), 7.29-7.22 (m, 4H), 4.53 (s, 2H), 3.44 (d,J=16.0 Hz, 2H), 3.29-3.26 (m, 2H), 2.91 (d, J=15.6 Hz, 2H), 1.81 (d,J=17.6 Hz, 4H). MS: (ES, m/z): 351 [M+H]⁺.

Example 11 Preparation of(S)-1′-benzyl-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide(I-35)

Step-1: Methyl(S)-1′-benzyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxylate

Into a 10-mL vial was placed a solution of the second eluted isomer fromExample 9 Step 4, which was assigned as methyl(S)-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxylate asdescribed above, (50 mg, 0.19 mmol, 1 equiv) in DMF (2 mL). This wasfollowed by the addition of NaH (60% in mineral oil, 8.47 mg, 0.18 mmol,1.1 equiv) in portions at 0° C. The resulting solution was stirred for30 min at 0° C. (Bromomethyl)benzene (35.7 mg, 0.21 mmol, 1.1 equiv) wasadded and the reaction was stirred for 2 h at 25° C. The reaction wasthen quenched by the addition of 10 mL of ice water. The reaction wasextracted with 2×15 mL of EtOAc. The combined organic layers were driedover Na₂SO₄, filtered and concentrated under vacuum to afford 50 mg (74%yield) of the title compound as a white solid. MS: (ES, m/z): 349[M+H]⁺.

Step-2:(S)-1′-Benzyl-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide

Into a 25-mL round-bottom flask was placed methyl(S)-1′-benzyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxylate(56 mg, 0.16 mmol, 1 equiv), THF/MeOH (4:1, 3.0 mL), NH₂OH (50% inwater, 516.78 mg, 10.12 mmol, 60 equiv), aq. 1N NaOH (0.3 mL, 0.26 mmol,2 equiv). The resulting solution was stirred for 2 h at 25° C. Thesolids were filtered out. The crude product was purified by Prep-HPLCwith the following conditions: Column: XBridge Prep C18 OBD, 19×150 mm,5 μm; Mobile Phase A: Water/0.1% Formic acid, Mobile Phase B: CH₃CN;Gradient: 5% B up to 64% B in 7 min; Detector: UV 254 nm, 220 nm. Thecollected fractions were lyophilized to afford the title compound as awhite solid. ¹H NMR (400 MHz, DMSO-d6) δ (ppm): 11.10 (s, 114), 8.95 (s,1H), 7.57 (s, 1H), 7.55-7.53 (d, J=8.0 Hz, 1H), 7.37-7.33(m, 2H),7.29-7.21 (m, 4H), 4.53 (s, 2H), 3.45-3.41 (d, 12.0 Hz, 2H), 3.27(s,2H), 2.93-2.89 (d, J=15.6 Hz, 2H), 1.78 (s, 4H). MS: (ES, m/z): 351[M+H]⁺.

Example 12 Preparation of(R)-N-hydroxy-2′-oxo-1′-phenyl-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide(I-36)

Step-1: Methyl(R)-2′-oxo-1′-phenyl-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxylate

Into a 25-mL round-bottom flask was placed the first eluted isomer fromExample 9 Step 4, which was assigned as methyl(R)-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxylate asdescribed above, (70 mg, 0.27 mmol, 1 equiv), THF (10 mL), Cu(OAc)₂ (49mg, 0.27 mmol, 1 equiv), pyridine (32 mg, 0.40 mmol, 1.5 equiv), Et₃N(82 mg, 0.81 mmol, 3 equiv) and phenylboronic acid (165 mg, 1.35 mmol, 5equiv). O₂ (g) was introduced to the flask and the reaction was stirredfor 48 h at 60° C. in an oil bath. The reaction was cooled to roomtemperature, filtered and concentrated under vacuum. The residue waspurified by normal phase chromatography on silica gel usingEtOAc/petroleum ether (1:2). The collected fractions were concentratedunder vacuum to afford 40 mg (44% yield) of the title compound as abrown oil. MS: (ES, m/z): 336 [M+H]⁺.

Step-2:(R)-N-Hydroxy-2′-oxo-1′-phenyl-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide

Into a 25-mL round-bottom flask was placed methyl(R)-2′-oxo-1′-phenyl-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxylate(40 mg, 0.12 mmol, 1 equiv), (4:1, 2.0 mL), NH₂OH (50% in water, 946 mg,120 equiv), aq. 1N NaOH (0.24 mL, 2 equiv). The resulting solution wasstirred for 2 h at 25° C. The solids were filtered out and the crudeproduct was purified by Prep-BPLC with the following conditions: Column:XBridge Prep C18 OBD, 19×150 mm, 5 μm; Mobile Phase A: Water/0.05%NH₄OH, Mobile phase B: CH₃CN; Gradient: 25% B up to 55% B in 7 min;Detector: UV 254 nm, 220 nm. The collected fractions were lyophilized toafford 8.0 mg (20% yield) of the title compound as a white solid. ¹H NMR(400 MHz, DMSO-d6) δ (ppm): 11.04 (s, 1H), 8.96 (s, 1H), 7.58-7.54 (m,2H), 7.40-7.36 (m, 2H), 7.29-7.22 (m, 4H), 3.70-3.67 (m, 2H), 3.50-3.45(m, 2H), 3.00-2.94 (m, 2H), 1.97-1.89 (m, 4H). MS: (ES, m/z): 337[M+H]⁺.

TABLE 6 The following compound was prepared according to the method ofExample 12, with stereochemistry assigned as described. Found (ES, m/z)Ex. Structure ¹H-NMR δ (ppm) [M + H]+ I-37

(400 MHz, DMSO-d6): 11.09 (s, 1H), 8.97 (s, 1H), 7.58 (s, 1H), 7.55-7.53(d, J = 7.6 Hz, 1H), 7.40-736 (m, 2H), 7.28-7.22 (m, 4H), 3.69-3.66 (m,2H), 3.49-3.44 (m, 2H), 2.99-2.94 (m, 2H), 1.98-190 (m, 4H) 337 In Step1, using 2^(nd) eluted isomer assigned as S

Example 13 In Vitro Histone Deacetylase Assay

The enzymatic HDAC6 assay was performed using electrophoretic mobilityshift assay. Full length human recombinant HDAC6 protein was expressedin baculoviral system and purified by affinity chromatography. Theenzymatic reactions were assembled in 384 well plates in a total volumeof 25 in a reaction buffer composing: 100 mM HEPES, pH 7.5, 25 mM KCl,0.1% bovine serum albumin, 0.01% Triton X-100, 1% DMSO (from compounds)2 μM of the fluorescently labeled peptide substrate and enzyme. Theenzyme was added at a final concentration of 1 nM. The peptide substrateRHKK(Ac)-NH₂ was used. The compounds were tested at 12 concentrationsspaced by 3× dilution intervals. Negative control samples (0%-inhibitionin the absence of inhibitor) and positive control samples(100%-inhibition) were assembled in replicates of four in each assayplate. The reactions were incubated at 25° C. and quenched by theaddition of 45 μL of termination buffer (100 mM HEPES, pH 7.5, 0.01%Triton X-100, 0.05% SDS).

The terminated assay plates were analyzed on LabChip® 3000 microfluidicelectrophoresis instrument (Perkin Elmer/Caliper Life Sciences). Thefluorescence intensity of the electrophoretically separatedde-acetylated product and substrate peptide was measured. Activity ineach sample was determined as the product to sum ratio (PSR): P/(S+P),where P is the peak height of the product peptide and S is the peakheight of the substrate peptide. Percent inhibition (Pinh) is determinedusing the following equation:

Pinh=(PSR 0%/−PSRinh)/(PSR 0%−PSR 100%)*100, where PSRinh is the productsum ratio in the presence of inhibitor, PSR 0% is the average productsum ration in the absence of inhibitor and PS 100% is the averageproduct sum ratio in 100%-inhibition control samples. The IC₅₀ values ofinhibitors were determined by fitting the %-inhibition curves with 4parameter dose-response model using XLfit 4 software.

As set forth in Table-7 below, IC₅₀ values are defined as follows:IC₅₀≤0.01 μM (+++); IC₅₀>0.01 μM and ≤0.05 μM(++); IC₅₀>0.05 μM (+).

TABLE7 Inhibitory Concentration (IC₅₀) Values for RepresentativeCompounds against HDAC6 HDAC6 activity IUPAC Name Number range(R)-N-hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro (I-1) ++[indene-2,3′-pyrrolidine]-5-carboxamide(S)-N-hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro (I-2) ++[indene-2,3′-pyrrolidine]-5-carboxamide(R)-N-hydroxy-1′-isopropyl-2′-oxo-1,3-dihydrospiro (I-3) ++[indene-2,3′-pyrrolidine]-5-carboxamide(S)-N-hydroxy-1′-isopropyl-2-oxo-1,3-dihydrospiro (I-4) +[indene-2,3′-pyrrolidine]-5-carboxamide(R)-1′-ethyl-N-hydroxy-2′-oxo-1,3-dihydrospiro (I-5) ++[indene-2,3′-pyrrolidine]-5-carboxamide (S)-1′-ethyl-N-hydroxy-2′-oxo-1,3-dihydrospiro (I-6) +[indene-2,3′-pyrrolidine]-5-carboxamide(R)-N-hydroxy-1′-isobutyl-2-oxo-1,3-dihydrospiro (I-7) ++[indene-2,3′-pyrrolidine]-5-carboxamide(S)-N-hydroxy-1′-isobutyl-2′-oxo-1,3-dihydrospiro (I-8) ++[indene-2,3′-pyrrolidine]-5-carboxamide(R)-N-hydroxy-1′-(2-methylbenzyl)-2′-oxo-1,3- (I-9) ++dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide(S)-N-hydroxy-1′-2-methylbenzyl)-2′-oxo-1,3- (I-10) ++dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide(R)-1′-benzyl-N-hydroxy-2-oxo-1,3-dihydrospiro (I-11) +++[indene-2,3′-pyrrolidine]-5-carboxamide(S)-1′-benzyl-N-hydroxy-2′-oxo-1,3-dihydrospiro (I-12) ++[indene-2,3′-pyrrolidine]-5-carboxamide(R)-N-hydroxy-2′-oxo-1′-phenyl-1,3-dihydrospiro (I-13) ++[indene-2,3′-pyrrolidine]-5-carboxamide(S)-N-hydroxy-2′-oxo-1′-phenyl-1,3-dihydrospiro (I-14) ++[indene-2,3′-pyrrolidine-5-carboxamide(R)-1′-(4-fluorophenyl)-N-hydroxy-2′-oxo-1,3- (I-15) ++dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide(S)-1′-(4-fluorophenyl)-N-hydroxy-2′-oxo-1,3- (I-16) ++ dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide(R)-N-hydroxy-2′-oxo-1′-(pyrrodin-3-yl)-1,3-dihydrospiro (I-17) +++[indene-2,3-pyrrolidine]-5-carboxamide(S)-N-hydroxy-2′-oxo-1′-(pyridin-3-yl)-1,3-dihydrospiro (I-18) ++[indene-2,3′-pyrrolidine]-5-carboxamide(R)-N-hydroxy-2′-oxo-1′-(pyridin-2-yl)-1,3-dihydrospiro (I-19) ++[indene-2,3′-pyrrolidine]-5-carboxamide(S)-N-hydroxy-2′-oxo-1′-(pyridin-2-yl)-1,3-dihydrospiro (I-20) ++[indene-2,3′-pyrrolidine]-5-carboxamide(R)-N-hydroxy-2′-oxo-1′-(pyridin-4-yl)-1,3-dihydrospiro (I-21) ++[indene-2,3′-pyrrolidine]-5-carboxamide(S)-N-hydroxy-2′-oxo-1′-(pyridin4-yl)-1,3-dihydrospiro (I-22) ++[indene-2,3′-pyrrolidine]-5-carboxamide(R)-N-hydroxy-2′-oxo-1′-(pyridin-3-ylmethyl)-1,3- (I-23) ++dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide(R)-N-hydroxy-1′-methyl-1,3-dihydrospiro[indene-2,3′- (I-24) ++pyrrolidine]-5-carboxamide(S)-N-hydroxy-1′-methyl-1,3-dihydrospiro[indene-2,3′- (I-25) +pyrrolidine]-5-carboxamide (R)-1′-benzyl-N-hydroxy-1,3-dihydrospiro[indene-2,3′- (I-26) ++ pyrrolidine]-5-carboxamide(S)-1′-benzyl-N-hydroxy-1,3-dihydrospiro[indene-2,3′- (I-27) ++pyrrolidine]-5-carboxamide(R)-1′-acetyl-N-hydroxy-1,3-dihydrospiro[indene-2,3′- (I-28) ++pyrrolidine-5-carboxamide(S)-1′-acetyl-N-hydroxy-1,3-dihydrospiro[indene-2,3′- (I-29) ++pyrrolidine]-5-carboxamide(R)-1′-benzoyl-N-hdroxy-1,3-dihydrospiro[indene-2,3′- (I-30) +++pyrrolidine]-5-carboxamide(S)-1′-benzoyl-N-hydroxy-1,3-dihydrospiro[indene-2,3′- (I-31) +++pyrrolidine]-5-carboxamide(R)-N-hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro (I-32) ++[indene-2,3′-piperidine-5-carboxamide(S)-N-hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro (I-33) ++[indene-2,3′-piperidine]-5-carboxamide(R)-1′-benzyl-N-hydroxy-2′-oxo-1,3 -dihydrospiro (I-34) +++[indene-2,3′-piperidine]-5-carboxamide(S)-1′-benzyl-N-hydroxy-2′-oxo-1,3-dihydrospiro (I-35) ++[indene-2,3′-piperidine]-5-carboxamide(R)-N-hydroxy-2′-oxo-1′-phenyl-1,3-dihydrospiro (I-36) +++[indene-2,3′-piperidine]-5-carboxamide(S)-N-hydroxy-2′-oxo-1′-phenyl-1,3-dihydrospiro (I-37) ++[indene-2,3′-piperidine]-5-carboxamide

Equivalents

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand other variations thereof will he apparent to those of ordinary skillin the art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

1. A compound of the Formula I:

or a pharmaceutically acceptable salt thereof, wherein: X¹, X², X³, X⁴,X⁵, and X⁶ are each independently, at each occurrence, —CR¹R²— or—C(O)—; Y¹, Y², Y³, and Y⁴ are each independently, at each occurrence, Nor CR¹, wherein —C(O)NHOH is attached at Y² or Y³, and Y² or Y³ is acarbon atom when attached to —C(O)NHOH; L is a bond, —(CR¹R²)_(p)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(p)O—,or —C(O)(CR¹R²)_(p)—; R is —H, —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl,—C₅-C₁₂spirocycloalkyl, heterocyclyl, spiroheterocyclyl, aryl, orheteroaryl containing 1-5 heteroatoms selected from the group consistingof N, S, P, or O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkyl, spirocycloalkyl, heterocyclyl, spiroheterocyclyl, aryl, orheteroaryl is optionally substituted with one or more —OH, halogen, oxo,—NO₂, —CN, —R¹, —R², —SR³, —OR³, —NHR³, —NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R¹,—C(O)R¹, —CO₂R¹, —NR³S(O)₂R¹, —S(O)R¹, —S(O)NR³R⁴, —NR³S(O)R¹,heterocyclyl, aryl, or heteroaryl; R¹ and R² are independently, at eachoccurrence, —H, —R³, —R⁴, —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, heterocyclyl, aryl,heteroaryl containing 1-5 heteroatoms selected from the group consistingof N, S, P and O, —OH, halogen, —NO₂, —CN, —NH(C₁-C₆alkyl),—N(C₁-C₆alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —N(C₁-C₆alkyl)S(O)₂R⁵,—S(O)₂(C₁-C₆alkyl), —(C₁-C₆alkyl)S(O)₂R⁵, —C(O)C₁-C₆alkyl,—CO₂C₁-C₆alkyl, —N(C₁-C₆alkyl)S(O)₂(C₁-C₆alkyl), or —(CHR⁵)_(p)NR³R⁴,wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore —OH, halogen, —NO₂, oxo, —CN, —R⁵, —OR³, —NHR³, —NR³R⁴,—S(O)₂N(R³)₂, —S(O)₂R⁵, —C(O)R⁵, —CO₂R⁵, —NR³S(O)₂R⁵, —S(O)R⁵,—S(O)NR³R⁴, —NR³S(O)R⁵, heterocyclyl, aryl, or heteroaryl; or R¹ and R²,when on the same atom, combine with the carbon atom to which they areattached to form a cycloalkyl, heterocyclyl, spirocycloalkyl,spiroheterocyclyl, or spirocycloalkenyl; or R¹ and R², when on adjacentor non-adjacent atoms, combine to form a heterocyclyl, cycloalkyl, aryl,heteroaryl containing 1-5 heteroatoms selected from the group consistingof N, S, P and O, or cycloalkenyl; R³ and R⁴ are independently, at eachoccurrence, —H, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₄-C₈cycloalkenyl,—C₂-C₆alkynyl, —C₃-C8cycloalkyl, heterocyclyl, aryl, heteroarylcontaining 1-5 heteroatoms selected from N, S, P, and O,—S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂(C₁-C₆alkyl), —(C₁-C₆alkyl)S(O)₂R⁵,—C(O)C₁-C₆alkyl, —CO₂C₁-C₆alkyl, or —(CHR⁵)_(p)N(C₁-C₆alkyl)₂, whereineach alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, and heteroaryl is optionally substituted with one or moresubstituents selected from —OH, halogen, —NO₂, oxo, —CN, —R⁵,—O(C₁-C₆alkyl), —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂,—S(O)₂NH(C₁-C₆alkyl), —C(O)C₁-C₆alkyl, —CO₂C₁-C₆alkyl,—N(C₁-C₆alkyl)S(O)₂(C₁-C₆alkyl), —S(O)R⁵, —S(O)N(C₁-C₆alkyl)₂,—N(C₁-C₆alkyl)S(O)R⁵, heterocyclyl, aryl, or heteroaryl; R⁵ isindependently, at each occurrence, —H, —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, heterocyclyl, aryl,heteroaryl containing 1-5 heteroatoms selected from N, S, P and O, —OH,halogen, —NO₂, —CN, —N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl),—S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂(C₁-C₆alkyl), —C(O)C₁-C₆alkyl,—CO₂C₁-C₆alkyl, —N(C₁-C₆alkyl)SO₂(C₁-C₆alkyl), —S(O)(C₁-C₆alkyl),—S(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl), or—(CH₂)_(p)N(C₁-C₆alkyl)₂; p is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, or 2;m is 0, 1, or 2; and wherein the sum m+n=2. 2-31. (canceled)
 32. Thecompound of claim 1, wherein n is
 0. 33. The compound of claim 1,wherein n is
 1. 34. The compound of claim 1, wherein X¹ is —CH₂— and X²is —CH₂—.
 35. The compound of claim 1, wherein X⁵ is —C(O)—.
 36. Thecompound of claim 34, wherein Y¹ and Y⁴ are each CR¹, wherein —C(O)NHOHis attached at Y² or Y³, and Y² or Y³ is a carbon atom when attached to—C(O)NHOH.
 37. The compound of claim 36, wherein L is a bond,—(CR¹R²)_(p)—, or —C(O)(CR¹R²)_(p)—.
 38. The compound of claim 37,wherein p is 0 or
 1. 39. The compound of claim 38, wherein R is —H or anoptionally substituted group selected from —C₁-C₆alkyl, aryl, andheteroaryl.
 40. The compound of claim 39, wherein R is an optionallysubstituted group selected from aryl or heteroaryl.
 41. The compound ofclaim 1, wherein the compound is of the Formula IA-3:


42. The compound of claim 1, wherein the compound is of the FormulaIA-5, Formula IA-6, Formula IA-7, or Formula IA-8:


43. The compound of claim 1, wherein the compound is of the FormulaIB-3, Formula IB-5, Formula IB-6, Formula IB-7, or Formula IB-8:


44. A compound of claim 1 selected from:(R)-N-hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide(I-32);(S)-N-hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide(I-33);(R)-1′-benzyl-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide(I-34);(S)-1′-benzyl-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide(I-35);(R)-N-hydroxy-2′-oxo-1′-phenyl-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide(I-36);(S)-N-hydroxy-2′-oxo-1′-phenyl-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide(I-37);N-hydroxy-1′-methyl-6′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide(I-39);N-hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-5-carboxamide(I-40);N-hydroxy-1′-methyl-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide(I-41); andN-hydroxy-1′-methyl-1,3-dihydrospiro[indene-2,4′-piperidine]-5-carboxamide(I-42).
 45. A pharmaceutical composition comprising a compound of claim1 and a pharmaceutically acceptable carrier.